2017 ESC focused update on dual antiplatelet

therapy in coronary artery disease developed

in collaboration with EACTS

The Task Force for dual antiplatelet therapy in coronary artery

disease of the European Society of Cardiology (ESC) and of the

European Association for Cardio-Thoracic Surgery (EACTS)

Authors/Task Force Members: Marco Valgimigli* (Chairperson) (Switzerland),

He´ctor Bueno (Spain), Robert A. Byrne (Germany), Jean-Philippe Collet (France),

Francesco Costa (Italy), Anders Jeppsson

(Sweden), Peter Ju¨ni (Canada),

Adnan Kastrati (Germany), Philippe Kolh (Belgium), Laura Mauri (USA),

Gilles Montalescot (France), Franz-Josef Neumann (Germany),

Mate Petricevic

(Croatia), Marco Roffi (Switzerland), Philippe Gabriel Steg

(France), Stephan Windecker (Switzerland), and Jose Luis Zamorano (Spain)

Additional Contributor: Glenn N. Levine (USA)

Document Reviewers: Lina Badimon (CPG Review Coordinator) (Spain), Pascal Vranckx (CPG Review

Coordinator) (Belgium), Stefan Agewall (Norway), Felicita Andreotti (Italy), Elliott Antman (USA),

Emanuele Barbato (Italy), Jean-Pierre Bassand (France), Raffaele Bugiardini (Italy), Mustafa Cikirikcioglu

(Switzerland), Thomas Cuisset (France), Michele De Bonis (Italy), Victora Delgado (The Netherlands),

Donna Fitzsimons (UK), Oliver Gaemperli (Switzerland), Nazzareno Galie` (Italy), Martine Gilard (France),

* Corresponding author: Marco Valgimigli, Cardiology, Inselspital, Freiburgstrasse 8, 3010 Bern, Switzerland. Tel: þ41 31 632 3077, Fax: þ41 10 7035258, E-mail: marco.valgimigli@insel.ch.

ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers: listed in the Appendix.

Representing the EACTS

ESC entities having participated in the development of this document:

Associations: Acute Cardiovascular Care Association (ACCA), European Association of Preventive Cardiology (EAPC), European Association of Percutaneous Cardiovascular

Interventions (EAPCI).

Working Groups: Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Coronary Pathophysiology and Microcirculation, Peripheral Circulation, Pulmonary Circulation and

Right Ventricular Function, Thrombosis, Valvular Heart Disease.

The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC

Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford

University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC (journals.permissions@oxfordjournals.org).

Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientiﬁc and medical knowledge and the evidence available

at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other ofﬁcial recom-

mendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encour-

aged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or

therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and

accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor do

the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant ofﬁcial updated recommendations or guidelines issued by the competent

public health authorities, in order to manage each patient’s case in light of the scientiﬁcally accepted data pursuant to their respective ethical and professional obligations. It is also the

health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

The article has been co-published with permission in the European Heart Journal [DOI: 10.1093/eurheartj/ehx419] on behalf of the European Society of Cardiology and

of European Heart Journal,

European Society of Cardiology 2017. The articles are identical except for minor stylistic and spelling differences in keeping with each journal’s

style. Either citation can be used when citing this article.

For permissions, please email journals.permissions@oup.com.

European Heart Journal (2018) 39, 213–254

ESC GUIDELINES

doi:10.1093/eurheartj/ehx419

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Christian W. Hamm (Germany), Borja Ibanez (Spain), Bernard Iung (France), Stefan James (Sweden),

Juhani Knuuti (Finland), Ulf Landmesser (Germany), Christ ophe Leclercq (France), Maddalena Lettino

(Italy), Gregory Lip (UK), Massimo Francesco Piepoli (Italy), Luc Pierard (Belgium),

Markus Schwerzmann (Switzerland), Udo Sechtem (Germany), Iain A. Simpson (UK), Miguel Sousa Uva

(Portugal), Eugenio Stabile (Italy), Robert F. Storey (UK), Michal Tendera (Pol and), Frans Van de Werf

(Belgium), Freek Verheugt (The Netherlands), and Victor Aboyans (CPG Supervisor) (France)

The disclosure forms of all experts involved in the development of this focused update are available on

the ESC website http://www.esc ardio.org/guidelines.

The Addenda and Clinical Cases companion document of this focused update are available at: www.escardio.

org/Guidelines/Clinical-Practice-Guidelines/2017-focused-update-on-dual-antiplatelet-therapy-dapt

Web addenda

Online publish-ahead-of-print 26 August 2017

............................ .......................... .................. .......................... ............................... ............. ............. .................. ......................

Keywords

Guidelines

•

Aspirin

•

Clopidogrel

•

Ticagrelor

•

Prasugrel

•

Dual antiplatelet therapy

•

Acute coronary

syndromes

•

Coronary artery bypass grafting

•

Coronary artery disease

•

Drug-eluting stents

•

Myocardial

infarction

•

Stent thrombosis

•

Bleeding

•

Percutaneous coronary intervention

•

Recommendation

•

Revascularization

•

Risk stratiﬁcation

•

Stents

•

Stable angina

•

Stable coronary artery disease

•

Oral

anticoagulant

•

Triple therapy

•

DAPT score

•

PRECISE-DAPT score

•

Non-cardiac surgery

Table of Contents

Abbreviationsandacronyms........................................215

1.Preamble........................................................216

2.Introduction.....................................................218

2.1 Short- and long-term outcomes after percutaneous coronary

intervention.....................................................219

2.2 Risk of stent thrombosis in relation to stent type. . . . . . . . . . . . . . .219

2.3 Short- and long-term outcomes after coronary artery bypass

surgery..........................................................219

2.4 Short- and long-term outcomes after medically managed acute

coronarysyndrome..............................................219

3. Efficacy and safety of dual antiplatelet therapy and risk

stratificationtools..................................................219

3.1 Dual antiplatelet therapy for the prevention of stent

thrombosis......................................................219

3.2 Dual antiplatelet therapy for the prevention of spontaneous

myocardialinfarction.............................................219

3.3 Dual antiplatelet therapy and mortality rate. . . . . . . . . . . . . . . . . . . .219

3.4Safetyofdualantiplatelettherapy.............................219

3.5 Risk stratification tools for ischaemia and bleeding risks . . . . . . . .219

3.6 Type of P2Y

inhibitorandtimingofinitiation.................221

3.7 Measures to minimize bleeding while on dual

antiplatelettherapy..............................................223

3.8 Switching between oral P2Y

inhibitors.......................225

4. Dual antiplatelet therapy and percutaneous coronary

intervention........................................................226

4.1 Dual antiplatelet therapy after percutaneous coronary

intervention for stable coronary artery disease . . . . . . . . . . . . . . . . . . . .226

4.2 Dual antiplatelet therapy after percutaneous coronary

interventionforacutecoronarysyndrome........................231

4.3Gapsintheevidence.........................................233

5. Dual antiplatelet therapy and cardiac surgery . . . . . . . . . . . . . . . . . . . . . .234

5.1 Dual antiplatelet therapy in patients treated with coronary

artery bypass surgery for stable coronary artery disease . . . . . . . . . . .234

5.2 Dual antiplatelet therapy in patients treated with coronary

artery bypass surgery for acute coronary syndrome . . . . . . . . . . . . . . .234

5.3 Dual antiplatelet therapy for prevention of graft occlusion. . . . . .237

5.4Gapsintheevidence .........................................237

6. Dual antiplatelet therapy for patients with medically managed

acutecoronarysyndrome..........................................237

7. Dual antiplatelet therapy for patients with indication for oral

anticoagulation.....................................................238

7.1 Risk stratification and strategies to improve outcome after

percutaneouscoronaryintervention..............................238

7.2Durationoftripletherapy ....................................239

7.3Cessationofallantiplateletagents.............................242

7.4Typeofanticoagulants........................................242

7.5Typeofstent.................................................242

8. Elective non-cardiac surgery in patients on dual antiplatelet

therapy............................................................242

9.Genderconsiderationandspecialpopulations.....................245

9.1Genderspecificities ..........................................245

9.2Diabetesmellitus.............................................245

9.3Lower-extremitiesarterydisease.............................245

9.4 Complex percutaneous coronary intervention . . . . . . . . . . . . . . . .248

9.5 Dual antiplatelet therapy decision making in patients with

stentthrombosis ................................................248

9.6 Patients who develop bleeding while on treatment. . . . . . . . . . . . .248

10.Keymessages...................................................249

11. Evidenced-based ‘to do and not to do’ messages . . . . . . . . . . . . . . . . .249

12. Web addenda and Clinical Cases companion document . . . . . . . . . .251

13.Appendix ......................................................251

14.References.....................................................252

214 ESC Guidelines

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Abbreviations and acronyms

ABC Age, Biomarkers (GDF-15, cTnT-hs, and

haemoglobin), and Clinical history

(previous bleeding)

ACCA Acute Cardiovascular Care Association

ACCOAST A Comparison of Prasugrel at the Time of

Percutaneous Coronary Intervention Or

as Pretreatment At the Time of Diagnosis

in Patients with Non-ST-Elevation

Myocardial Infarction

ACS Acute coronary syndrome

ADP Adenosine 5’-diphosphate

AF Atrial ﬁbrillation

ANTARCTIC Platelet Function Monitoring to Adjust

Antiplatelet Therapy in Elderly Patients

Stented for an Acute Coronary Syndrome

ARCTIC-Interruption Assessment by a Double Randomisation of a

Conventional Antiplatelet Strategy Versus a

Monitoring-Guided Strategy for Drug-

Eluting Stent Implantation and, of Treatment

Interruption Versus Continuation 1 Year

After Stenting-Interruption

ART Arterial Revascularisation Trial

ASA Acetylsalicylic acid

ATACAS Aspirin and Tranexamic Acid for

Coronary Artery Surgery

ATLANTIC Administration of Ticagrelor in the Cath

Lab or in the Ambulance for New ST

Elevation Myocardial Infarction to Open

the Coronary Artery

BARC Bleeding Academic Research Consortium

b.i.d Bis in die (twice a day)

BMS Bare-metal stent

CABG Coronary artery bypass graft surgery

CAD Coronary artery disease

CHADS

Cardiac failure, Hypertension, Age,

Diabetes, Stroke (Doubled)

CHA

-VASc Cardiac failure, Hypertension, Age >_75(2

points), Diabetes, Stroke (2 points)– Vascular

disease, Age 65– 74, Sex category

CHARISMA Clopidogrel for High Atherothrombotic

Risk and Ischemic Stabilization,

Management, and Avoidance

CI Conﬁdence interval

COGENT Clopidogrel and the Optimization of

Gastrointestinal Events Trial

CORONARY CABG Off or On Pump Revascularization

Study

CPG Committee for Practice Guidelines

CrCl Creatinine clearance

CREDO Clopidogrel for the Reduction of Events

During Observation

CRUSADE Can Rapid risk stratiﬁcation of Unstable

angina patients Suppress ADverse

outcomes with Early implementation of

the ACC/AHA Guidelines

CURE Clopidogrel in Unstable Angina to Prevent

Recurrent Events

CYP Cytochrome P450

DAPT Dual antiplatelet therapy

DES Drug-eluting stent

EACTS European Association for Cardio-Thoracic

Surgery

EAPC European Association of Preventive

Cardiology

EAPCI European Association of Percutaneous

Cardiovascular Interventions

ESC European Society of Cardiology

EXAMINATION Clinical Evaluation of the Xience-V stent

in Acute Myocardial INfArcTION

EXCELLENT Efﬁcacy of Xience/Promus Versus Cypher

to Reduce Late Loss After Stenting

FDA Food and Drug Administration

GUSTO Global Use of Strategies to Open

Occluded Coronary Arteries

HAS-BLED Hypertension, Abnormal renal and liver

function, Stroke, Bleeding history or

predisposition, Labile INR, Elderly

(> 65 years), Drugs and alcohol

HR Hazard ratio

I-LOVE-IT 2 Evaluate Safety and Effectiveness of the

Tivoli DES and the Firebird DES for

Treatment of Coronary Revascularization

INR International normalized ratio

ISAR Intracoronary Stenting and

Antithrombotic Regimen

ISAR-SAFE Intracoronary Stenting and

Antithrombotic Regimen: Safety and

Efﬁcacy of 6 Months Dual Antiplatelet

Therapy After Drug-Eluting Stenting

ISAR-TRIPLE Intracoronary Stenting and

Antithrombotic Regimen– Testing of a 6-

Week Versus a 6-Month Clopidogrel

Treatment Regimen in Patients With

Concomitant Aspirin and Oral

Anticoagulant Therapy Following Drug-

Eluting Stenting

ITALIC Is There a Life for DES After

Discontinuation of Clopidogrel

IVUS XPL Impact of Intravascular Ultrasound

Guidance on Outcomes of XIENCE

PRIME Stents in Long Lesions

LATE Late coronary Arterial Thrombotic Events

LEAD Lower-extremities artery disease

LEADERS-FREE Prospective randomized comparison of

the BioFreedom biolimus A9 drug-coated

stent versus the gazelle bare-metal stent

in patients at high bleeding risk

LVEF Left ventricular ejection fraction

MACCE Major adverse cardiac and

cerebrovascular events

MACE Major adverse cardiovascular events

ESC Guidelines 215

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MATRIX Minimizing Adverse Haemorrhagic Events

by TRansradial Access Site and Systemic

Implementation of angioX

MI Myocardial infarction

NACE Net adverse clinical events

NCDR National Cardiovascular Data Registry

NNT Number needed to treat

NOAC Non-vitamin K oral anticoagulant

NORSTENT NORwegian coronary STENT trial

NSTE-ACS Non-ST elevation acute coronary syndrome

NSTEMI Non-ST-segment elevation myocardial

infarction

OAC Oral anticoagulant

o.d. Omni die (once a day)

OPTIMIZE Optimized Duration of Clopidogrel

Therapy Following Treatment With the

Zotarolimus-Eluting Stent in Real-World

Clinical Practice

OR Odds ratio

PARIS Patterns of Nonadherence to Antiplatelet

Regimens in Stented Patients

PCI Percutaneous coronary intervention

PEGASUS-TIMI 54 Prevention of Cardiovascular Events in

Patients with Prior Heart Attack Using

Ticagrelor Compared to Placebo on a

Background of Aspirin– Thrombolysis in

Myocardial Infarction 54

PIONEER AF-PCI Rivaroxaban and a dose- adjusted oral

vitamin K antagonist treatment strategy in

subjects with atrial ﬁbrillation who

undergo percutaneous coronary

intervention

PLATO PLATelet inhibition and patient Outcomes

PPI Proton pump inhibitor

PRECISE-DAPT PREdicting bleeding Complications In

patients undergoing Stent implantation

and subsEquent Dual Anti Platelet

Therapy

PRODIGY PROlonging Dual antiplatelet treatment

after Grading stent-induced intimal

hYperplasia study

PROTECT Patient-Related Outcomes With Endeavor

vs Cypher Stenting

q.d. Quaque die (one a day)

RCT Randomized controlled trial

REDUAL-PCI Evaluation of Dual Therapy With

Dabigatran vs. Triple Therapy With

Warfarin in Patients With AFib That

Undergo a PCI With Stenting

RESET Real Safety and Efﬁcacy of 3-Month Dual

Antiplatelet Therapy Following Endeavor

Zotarolimus-Eluting Stent Implantation

ROOBY Veterans Affairs Randomized On/Off

Bypass trial

RR Relative risk

RRR Relative risk reduction

SECURITY Second Generation Drug-Eluting Stent

Implantation Followed by Six- Versus

Twelve-Month Dual Antiplatelet Therapy

STEMI ST-segment elevation myocardial

infarction

STREAM STrategic Reperfusion Early After

Myocardial Infarction

SYNTAX Synergy Between Percutaneous Coronary

Intervention With Taxus and Cardiac

Surgery

TIA Transient ischaemic attack

TIMI Thrombolysis In Myocardial Infarction

TL-PAS Taxus Liberte´ Post Approval Study

TRA 2



P-TIMI 50 Thrombin Receptor Antagonist in

Secondary Prevention of

Atherothrombotic Ischemic Events

TRACER Thrombin Receptor Antagonist for

Clinical Event Reduction in Acute

Coronary Syndrome

TRILOGY ACS Targeted Platelet Inhibition to Clarify the

Optimal Strategy to Medically Manage

Acute Coronary Syndromes

TRITON-TIMI 38 Trial to Assess Improvement in Therapeutic

Outcomes by Optimizing Platelet Inhibition

with Prasugrel– Thrombolysis in Myocardial

Infarction

TROPICAL-ACS Testing Responsiveness to Platelet

Inhibition on Chronic Antiplatelet

Treatment For Acute Coronary

Syndromes Trial

VA Veterans’ Administration

VKA Vitamin K antagonist

WOEST What is the Optimal antiplatElet and

anticoagulant therapy in patients with

OAC and coronary StenTing

ZES Zotarolimus-eluting stent

ZEUS Zotarolimus-eluting Endeavor sprint stent

in Uncertain DES Candidates

24/7 24 h a day, seven days a week

1. Preamble

Guidelines and Focused Updates written under the auspices of the

European Society of Cardiology’s (ESC) Committee for Practice

Guidelines (CPG) summarize and evaluate available evidence with

the aim of assisting health professionals in selecting the best manage-

ment strategies for an individual patient with a given condition. The

CPG Guidelines’ and Focused Updates’ recommendations should

facilitate decision making of health professionals in their daily practice.

However, the final decisions concerning an individual patient must be

made by the responsible health professional(s) in consultation with

the patient and caregiver as appropriate.

A great number of guidelines and focused updates have been

issued in recent years by the ESC and by the European

Association for Cardio-Thoracic Surgery (EACTS) as well as by

other societies and organizations. Because of the impact on

216 ESC Guidelines

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clinical practice, quality criteria for the development of guidelines

have been established in order to make all decisions transparent

to the user. The recommendations for formulating and issuing

ESC Guidelines can be found on the ESC website (http://www.

escardio.org/Guidelines-&-Education/Clinical-Practice-Guidelines/

Guidelines-development/Writing-ESC-Guidelines). ESC Guidelines

represent the official position of the ESC on a given topic and

are regularly updated.

Members of this Task Force were selected by the ESC and EACTS

to represent professionals involved with the medical care of patients

with this pathology. Selected experts in the field undertook a com-

prehensive review of the published evidence for management of a

given condition according to ESC Committee for Practice Guidelines

(CPG) policy and approved by the EACTS. A critical evaluation of

diagnostic and therapeutic procedures was performed, including

assessment of the risk–benefit ratio. The level of evidence and the

strength of the recommendation of particular management options

were weighed and graded according to predefined scales, as outlined

in Tables 1 and 2.

The experts of the writing and reviewing panels provided declara-

tion of interest forms for all relationships that might be perceived as

real or potential sources of conflicts of interest. These forms were

compiled into one file and can be found on the ESC website (http://

www.escardio.org/guidelines). Any changes in declarations of interest

that arise during the writing period were notified to the ESC and

updated. The Task Force received its entire financial support from

the ESC without any involvement from the healthcare industry.

The ESC CPG supervises and coordinates the preparation of new

Guidelines and of its Focused Updates. The Committee is also

responsible for the endorsement process of these documents. These

CPG documents undergo extensive review by the CPG and external

experts, and in this case by EACTS-appointed experts. After appro-

priate revisions the CPG documents are approved by all the experts

involved in the Task Force. The finalized document is approved by

the CPG for publication in the European Heart Journal and in the

European Journal of Cardio-Thoracic Surgery. These CPG docu-

ments were developed after careful consideration of the scientific

and medical knowledge and the evidence available at the time of their

dating.

The task of developing this CPG Focused Update in collaboration

with EACTS also includes the creation of educational tools and

implementation programmes for the recommendations including

condensed pocket guideline versions, summary slides, and an elec-

tronic version for digital applications (smartphones, etc.) as well as

other educational tools depending on the topic. These versions are

abridged and thus, if needed, one should always refer to the full text

version, which is freely available via the ESC website and hosted on

the EHJ website. The National Societies of the ESC are encouraged

Table 1 Classes of recommendations

Table 2 Levels of evidence

ESC Guidelines 217

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to endorse, translate and implement all ESC Guidelines.

Implementation programmes are needed because it has been shown

that the outcome of disease may be favourably influenced by the

thorough application of clinical recommendations.

Surveys and registries are needed to verify that real-life daily prac-

tice is in keeping with what is recommended in the guidelines, thus

completing the loop between clinical research, writing of guidelines

and official focused updates, disseminating them and implementing

them into clinical practice.

Health professionals are encouraged to take the ESC CPG

Guidelines and Focused Updates developed in collaboration with

EACTS fully into account when exercising their clinical judgment, as

well as in the determination and the implementation of preventive,

diagnostic or therapeutic medical strategies. However, the CPG

documents do not override in any way whatsoever the individual

responsibility of health professionals to make appropriate and accu-

rate decisions in consideration of each patient’s health condition and

in consultation with that patient or the patient’s caregiver where

appropriate and/or necessary. It is also the health professional’s

responsibility to verify the rules and regulations applicable to drugs

and devices at the time of prescription.

2. Introduction

The estimated number of patients requiring dual antiplatelet therapy

(DAPT), consisting of the combination of aspirin and an oral inhibitor

of the platelet P2Y

receptor for adenosine 5’-diphosphate (ADP), is

considerable and has increased over time in Europe. Based on popu-

lation estimates from 2015, in the region of 1 400 000 and 2 200 000

patients per year may have an indication for DAPT after coronary

intervention or myocardial infarction (MI), respectively.

This year, 2017, is the 21st anniversary of the publication of the

first randomized clinical trial to establish the superiority of DAPT

over anticoagulant therapy among patients undergoing percutaneous

coronary intervention (PCI) (Figure 1).

Basedonover35random-

ized clinical trials, including more than 225 000 patients, DAPT is

among the most intensively investigated treatment options in the field

of cardiovascular medicine. Along with progressive refinement of

P2Y

inhibition strategies—embracing firstly safer (from ticlopidine

to clopidogrel) and then more potent and predictable (from clopi-

dogrel to ticagrelor or prasugrel) drugs—research has concomitantly

focused on optimal treatment duration. The need to investigate lon-

ger DAPT regimens firstly arose from concerns over late and very

Figure 1 History of dual antiplatelet therapy (DAPT) in patients with coronary artery disease. The size of the circles denotes sample size. The col-

ours of perimeters identify the type of included patient populations within each study. The colours within each circle identify the antiplatelet agent(s)

investigated. Head-to-head studies comparing similar durations of two different antiplatelet strategies are shown with a vertical line, whereas those

investigating different treatment durations are shown with a horizontal line. Studies investigating different treatment strategies or regimens and not

treatment durations or type (e.g. pre-treatment in ACCOAST, tailored therapy in GRAVITAS, double dose of clopidogrel in CURRENT OASIS 7,

etc.) are represented with a single colour indicating the P2Y

inhibitor, which was tested on top of aspirin.

pts = patients.

218 ESC Guidelines

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late stent thrombosis occurring after first-generation drug-eluting

stent (DES) implantation.

Yet, the advent of safer newer-generation

DESs and the results of the most recent randomized controlled trials

(RCTs) have established a major paradigm shift in the way DAPT

should be conceived and used in clinical practice. DAPT remains a

highly effective preventive treatment for stent thrombosis across the

board; however, the risks of late and (even more) very late stent

thrombosis have declined considerably since the advent of newer-

generation DESs. Hence, the risk of bleeding associated with DAPT

prolongation beyond 1 year does not seem to be justified by the small

absolute benefit observed in terms of very late stent thrombosis pre-

vention. On the other hand, there is emerging evidence that DAPT

reduces the long-term risk of non-stent-related MI as well as stroke.

Hence, after 21 years of research, DAPT has moved from a local (i.e.

stent-related) to a systemic treatment strategy (i.e. capable of pre-

venting thrombotic arterial vessel occlusion), conveying global

patient protection (Figure 1).

There is, however, confusion in the community around the optimal

type and duration of DAPT in patients with established coronary

artery disease (CAD), undergoing coronary revascularization or

not.

This derives from apparently conflicting results arising from the

available studies and limited evidence on various patient subsets (e.g.

elderly patients, with comorbidities or at greater bleeding risk) in

whom the trade-off between the benefits and risks of DAPT may dif-

fer from those observed in more selected patient cohorts included in

trials. Therefore, the scope of this focused update is to address rec-

ommendations on DAPT in patients with CAD.

2.1 Short- and long-term outcomes after

percutaneous coronary intervention

See Web Addenda.

2.2 Risk of stent thrombosis in relation to

stent type

See Web Addenda.

2.3 Short- and long-term outcomes after

coronary artery bypass surgery

See Web Addenda.

2.4 Short- and long-term outcomes after

medically managed acute coronary

syndrome

See Web Addenda.

3. Efficacy and safety of dual

antiplatelet therapy and risk

stratification tools

Current evidence suggests that DAPT mitigates the risk of stent

thrombosis across the whole spectrum, from acute to very late

events. However, treatment with DAPT beyond 1 year after MI, or

after PCI, exerts the majority of its benefit by reducing the rate of

spontaneous MI, which is associated with mortality rates of 15%.

Nonetheless, because continued antiplatelet therapy is also associ-

ated with increased bleeding risk, it is necessary to weigh this risk

against the potential benefit. Current evidence suggests that the risk

of bleeding in patients on DAPT is proportionally related to its dura-

tion both within and beyond 1 year of treatment duration. Since the

benefits of prolonged DAPT, especially for mortality endpoints,

appear highly dependent on prior cardiovascular history [such as

prior acute coronary syndrome (ACS)/MI vs. stable CAD], and pre-

diction models to estimate on-DAPT bleeding risk have been devel-

oped, an individualized approach based on ischaemic vs. bleeding risk

assessment is warranted.

3.1 Dual antiplatelet therapy for the

prevention of stent thrombosis

See Web Addenda.

3.2 Dual antiplatelet therapy for the

prevention of spontaneous myocardial

infarction

See Web Addenda.

3.3 Dual antiplatelet therapy and

mortality rate

See Web Addenda.

3.4 Safety of dual antiplatelet therapy

See Web Addenda.

3.5 Risk stratification tools for ischaemia

and bleeding risks

Given the trade-off between ischaemic vs. bleeding risks for any given

DAPT duration, the use of scores might prove useful to tailor DAPT

duration in order to maximize ischaemic protection and minimize

bleeding risks in the individual patient.

Most of the frequently used

risk scores for assessing ischaemic events

7–9

and major bleeds

10–12

were originally developed and validated for the prediction of events

occurring mainly during hospital stay or early on thereafter.

13,14

As a

result, the application of these risk scores to decide upon DAPT

duration remains problematic, as only limited data exist exploring

their value to guide DAPT duration.

On the other hand, the use of

risk scores that were specifically designed to guide and inform deci-

sion making on DAPT duration should be prioritized over other avail-

able risk scores (Table 3).

The DAPT score was developed from 11 648 patients enrolled in

the DAPT trial and was initially validated in 8136 patients enrolled in

the Patient-Related Outcomes With Endeavor vs. Cypher Stenting

(PROTECT) trial.

This prediction rule identified nine factors [age,

congestive heart failure/low left ventricular ejection fraction (LVEF),

vein graft stenting, MI at presentation, prior MI or PCI, diabetes, stent

diameter <3 mm, smoking, and paclitaxel-eluting stent] resulting in a

score ranging from -2 to þ 10. Within the DAPT trial, a high-risk

score (i.e. a score >_2) selected patients who showed a reduction in

MI/stent thrombosis and cardiovascular or cerebrovascular events

risk [number needed to treat (NNT) for benefit for ischaemic event

reduction = 34] after a prolonged, 30-month DAPT, with only a

modest increase in bleeding risk (NNT for harm = 272). In turn, a

ESC Guidelines 219

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low-risk score (<2) selected patients recruited in the DAPT trial who

did not derive any reduction of ischaemic events from prolonging

DAPT, with a significant increase in moderate/major bleeding (NNT

for harm = 64). As DAPT duration was not randomized in the

PROTECT trial, the value of the DAPT score in guiding the duration

of therapy has so far only been shown for patients recruited to the

DAPT trial. Additional validation of the DAPT score to guide DAPT

duration is needed, especially in the context of less well-selected

patients as compared to those recruited in the DAPT trial and under-

going treatment with new-generation DES only.

Two independent predictive scores for bleeding [age, body mass

index, smoking, anaemia, creatinine clearance (CrCl), and triple ther-

apy at discharge] and MI or stent thrombosis [diabetes mellitus, ACS,

smoking, CrCl, prior PCI, and prior coronary artery bypass graft sur-

gery (CABG)] have also been developed from the Patterns of

Nonadherence to Antiplatelet Regimens in Stented Patients (PARIS)

registry.

PARIS was a prospective, multicentre, observational study

of patients undergoing PCI with stent implantation in the USA and

Europe, which was designed to examine the different modes of

DAPT cessation and to investigate the influence of these modes on

subsequent clinical adverse events.

This registry study included

patients with an indication for oral anticoagulation. The value of the

PARIS bleeding and/or ischaemic risk scores to tailor DAPT duration

remains unclear, since therapy duration was not randomized in the

PARIS study and no study to date has applied the results of these

scores for DAPT type or duration guidance. A high ischaemic risk sta-

tus was observed in roughly 40% of high bleeding risk patients

and

as many as 65.3% presented low ischaemic and bleeding risks.

Therefore, it remains unclear how DAPT duration should be guided

by the simultaneous assessment of ischaemic and bleeding risk fea-

tures according to PARIS.

The PRECISE-DAPT (PREdicting bleeding Complications In

patients undergoing Stent implantation and subsEquent Dual Anti

Platelet Therapy) collaborative study included a total of 14 963

patients with CAD who underwent elective, urgent, or emergent PCI

and generated a five-item (age, CrCl, haemoglobin, white blood cell

count, and prior spontaneous bleeding) prediction algorithm for out-

of-hospital bleeding in patients treated with DAPT.

The predictive performance of this novel score was assessed in the

derivation cohort and validated in 8595 and 6172 patients treated with

PCI from the PLATelet inhibition and patient Outcomes (PLATO) trial

and the Bern PCI registry,

19,20

respectively. The PRECISE-DAPT score

showed improved integrated discrimination and reclassification per-

formance as compared to the PARIS bleeding score in both validation

cohorts.

The usefulness of this score was also assessed within

patients randomized to different DAPT durations (n =10081)toiden-

tify the effect on bleeding and ischaemia of a long (12–24 months) or

short (3–6 months) treatment duration in relation to baseline bleeding

risk. It was observed that among patients deemed at high bleeding risk

based on PRECISE-DAPT (PRECISE-DAPT score >_25), prolonged

Table 3 Risk scores validated for dual antiplatelet therapy duration decision-making

CHF = congestive heart failure; CrCl = creatinine clearance; DAPT = dual antiplatelet therapy; Hb = haemoglobin; LVEF = left ventricular ejection fraction; MI = myocardial

infarction; PCI = percutaneous coronary intervention; PRECISE-DAPT = PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual

Anti Platelet Therapy; WBC = white blood cell count.

For the PRECISE-DAPT score use the score nomogram: mark patient’s value for each of the ﬁve clinical variables of the score and draw a vertical line to the ‘Point’ axis to

determine the number of points obtained for each clinical variable. Then summate the points obtained for each clinical variable to the total score. A practical case example for

score calculation is provided in Web Figure 1 of the Web Addenda.

For the DAPT score summate positive points for each value and subtract values for age to the total score.

220 ESC Guidelines

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DAPT was associated with no ischaemic benefit but a remarkable

bleeding burden leading to an NNT for harm of 38.

On the other

hand, longer treatment in patients without high bleeding risk

(PRECISE-DAPT score <25) was associated with no increase in bleed-

ing and a significant reduction in the composite ischaemic endpoint of

MI, definite stent thrombosis, stroke, and target vessel revasculariza-

tion,withanNNTforbenefitof65.

Selecting a shorter than 12-

month treatment duration in patients deemed at high bleeding risk

upfront may therefore prevent their exposure to an excessive bleeding

hazard. In turn, patients at non-high bleeding risk might receive a stand-

ard (i.e. 12 months) or prolonged (i.e. >12 months) course of treat-

ment if tolerated.

However, none of these risk prediction models have been pro-

spectively tested in the setting of RCTs. Therefore, their value in

improving patient outcomes remains unclear.

3.6 Type of P2Y

inhibitor and timing of

initiation

Clopidogrel: Clopidogrel is associated with a better safety profile than

ticlopidine, mainly in terms of allergy, skin or gastrointestinal disor-

ders, and neutropenia, while it has a similar degree and consistency of

P2Y

inhibition and bleeding risk.

21,22

The wide variability in the

pharmacodynamic response to ticlopidine and clopidogrel is linked

to several factors, including genotype polymorphisms.

Clinical evi-

dence with respect to the optimal duration of clopidogrel therapy

after PCI is discussed elsewhere (Chapter 4).

Prasugrel: Prasugrel achieves a faster, greater, and more consistent

degree of P2Y

inhibition as compared to clopidogrel. Prasugrel

requires two metabolic steps for formation of its active metabolite,

which is chemically similar to the active metabolite of clopidogrel.

The Trial to Assess Improvement in Therapeutic Outcomes by

Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in

Myocardial Infarction (TRITON-TIMI 38) included P2Y

inhibitor-

naı¨ve ACS patients in whom coronary anatomy was deemed suitable

for PCI, or patients with ST-segment elevation myocardial infarction

(STEMI) referred for primary PCI.

Duration of DAPT was up to

15 months in both study arms. The composite primary endpoint (car-

diovascular death, non-fatal MI, or stroke) occurred in 9.3% of

prasugrel-treated patients vs. 11.2% of clopidogrel-treated patients

[hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.73–0.93; P =

0.002], mostly driven by a significant risk reduction for MI [from 9.2%

to 7.1%; relative risk reduction (RRR) 23.9%, 95% CI 12.7–33.7; P <

0.001).

There was no difference in the rates of either non-fatal

stroke or cardiovascular death.

Prasugrel was associated with a significant increase in the rate of

non-CABG-related TIMI major bleeding (2.4% vs. 1.8%; HR 1.32, 95%

CI 1.03–1.68; P = 0.03). Life-threatening bleeding was significantly

increased under prasugrel compared with clopidogrel (1.4% vs. 0.9%;

HR 1.52, 95% CI 1.08–2.13; P = 0.01), as was fatal bleeding (0.4% vs.

0.1%, HR 4.19, 95% CI 1.58–11.11; P = 0.002). CABG-related bleed-

ing was also higher in prasugrel-treated patients (13.4% vs. 3.2%; HR

4.72, 95% CI 1.90–11.82; P < 0.001). There was evidence of net harm

with prasugrel in patients with a history of cerebrovascular events. In

addition, there was no apparent net clinical benefit in patients

>_75 years of age and in patients with low body weight (<60 kg).

Prasugrel was not tested in medically managed ACS patients in the

setting of the TRITON-TIMI 38 study. In the Targeted Platelet

Inhibition to Clarify the Optimal Strategy to Medically Manage Acute

Coronary Syndromes (TRILOGY ACS) study, which exclusively

included medically managed ACS patients, the primary endpoint of

death from cardiovascular causes, MI, or stroke among patients

under the age of 75 years occurred in 13.9% of the prasugrel group

and 16.0% of the clopidogrel group (HR 0.91, 95% CI 0.79–1.05; P =

0.21), at a median follow-up of 17 months.

Similar results were

observed in the overall population (i.e. also including elderly patients).

Hence, prasugrel is not indicated in medically managed ACS patients.

The TRITON-TIMI 38 study mandated the use of prasugrel or clo-

pidogrel after coronary angiography if an indication to proceed to

PCI was established. Pre-treatment was allowed only in STEMI

patients undergoing primary intervention (n = 2438).

For the comparison of prasugrel at the time of PCI, in the A

Comparison of Prasugrel at the Time of Percutaneous Coronary

Intervention Or as Pretreatment At the Time of Diagnosis in Patients

with Non-ST-Elevation Myocardial Infarction (ACCOAST), 4033

patients with non-STEMI (NSTEMI) who were scheduled to undergo

coronary angiography within 2–48 h after randomization were assigned

to receive prasugrel (a 30 mg loading dose) before angiography (pre-

treatment group) or placebo (control group).

When PCI was indi-

cated, an additional 30 mg of prasugrel was given in the pre-treatment

group at the time of PCI and 60 mg of prasugrel was given in the control

group. The rate of the primary efficacy endpoint, a composite of death

from cardiovascular causes, MI, stroke, urgent revascularization, or gly-

coprotein IIb/IIIa inhibitor rescue therapy (glycoprotein IIb/IIIa bailout)

through day 7, did not differ significantly between the two groups (HR

with pre-treatment 1.02, 95% CI 0.84–1.25; P = 0.81).

The rate of the

key safety endpoint of all TIMI major bleeding episodes, whether related

toCABGornot,throughday7wasincreasedwithpre-treatment(HR

1.90, 95% CI 1.19–3.02; P = 0.006). The rates of TIMI major bleeding

and life-threatening bleeding not related to CABG were increased by a

factor of 3 and 6, respectively. Pre-treatment did not reduce the rate of

the primary outcome among patients undergoing PCI (69% of the

patients) but increased the rate of TIMI major bleeding at 7 days.

Hence, prasugrel is not indicated in patients with ACS in whom cor-

onary anatomy is not known and an indication for PCI is not clearly

established, with the exception of STEMI patients scheduled to undergo

immediate coronary catheterization and PCI, if clinically indicated.

In the DAPT trial, 3461 patients (34.7% of the total trial population)

who were treated with prasugrel within the first 12 months after

Use of risk scores as guidance for the duration of dual

antiplatelet therapy

Recommendations Class

Level

The use of risk scores designed to evaluate

the beneﬁts and risks of different DAPT

durations

may be considered.

15,18

IIb A

DAPT = dual antiplatelet therapy.

Class of recommendation.

Level of evidence.

The DAPT and PRECISE-DAPT scores are those currently fulﬁlling these

requirements.

ESC Guidelines 221

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intervention were randomly allocated to stop or continue the treat-

ment for an additional 18 months.

ThetypeofP2Y

inhibitor or stent

type were not randomized for. However, the largest cohort of prasu-

grel-treated patients (n = 2191) was provided by the TAXUS Liberte´

Post Approval Study (TL-PAS), which was a prospective, multicentre,

open-label study developed to review the clinical performance of the

Taxus Liberte´ paclitaxel-eluting stent in routine clinical practice in the

USA.

Enrolled TL-PAS patients received open-label prasugrel plus

aspirin for 12 months after stent placement; enrolment was not

restricted to patients presenting with ACS (i.e. those with an approved

indication for prasugrel). Rates of death and stroke were similar

between groups, but MI was significantly reduced with prolonged prasu-

grel treatment (1.9% vs. 7.1%; HR 0.255; P < 0.001). The DAPT co-

primary endpoint, stent thrombosis, was also lower with longer therapy

(0.2% vs. 2.9%; HR 0.063; P < 0.001). The safety endpoint of GUSTO

(Global Use of Strategies to Open Occluded Coronary Arteries) mod-

erate or severe bleeding was numerically increased in the patients con-

tinuing prasugrel to 30 months, although the difference was not

statistically significant (2.4% vs. 1.7%; HR 1.438; P =0.234).

No sub-

group data have been provided among patients treated with prasugrel

with respect to indication for PCI (i.e. ACS vs. stable CAD) or type of

implanted stent (i.e. paclitaxel-eluting stent vs. other stent types).

Ticagrelor: Ticagrelor belongs to a novel chemical class, cyclopentyl

triazolopyrimidine, and is a direct oral, reversibly binding P2Y

inhibi-

tor with a plasma half-life of 12 h. In the PLATO trial, ticagrelor

proved to be superior to clopidogrel in ACS patients, who were

allowed to be pre-treated with clopidogrel at hospital admission, irre-

spective of the final revascularization strategy (i.e. planned or not

planned invasive management).

Patients with either moderate- to

high-risk non-ST elevation ACS (NSTE-ACS) (planned for either

conservative or invasive management) or STEMI planned for primary

PCI were randomized to either clopidogrel 75 mg daily, with a loading

dose of 300 mg, or ticagrelor 180 mg loading dose followed by 90 mg

twice daily.

Patients undergoing PCI were allowed to receive an

additional blinded 300 mg loading dose of clopidogrel (total loading

dose 600 mg) or its placebo, and were also recommended to receive

an additional 90 mg of ticagrelor (or its placebo) if > 24 h after the ini-

tial loading dose. Treatment was continued for up to 12 months, with

a minimum intended treatment duration of 6 months and a median

duration of study drug exposure of 9 months.

In the overall cohort, the primary composite efficacy endpoint

(death from vascular causes, MI, or stroke) was observed in 9.8% of

the patients in the ticagrelor group and in 11.7% of the patients in the

clopidogrel group (HR 0.84, 95% CI 0.77–0.92; P < 0.001).

According to the pre-defined statistical analysis plan, death from vas-

cular causes was significantly reduced from 5.1% to 4.0% (HR 0.79,

95% CI 0.69–0.91; P = 0.001), and from MI from 6.9% to 5.8% (HR

0.84, 95% CI 0.75–0.95; P = 0.005). There was no significant difference

in the rates of stroke (1.3% vs. 1.5%; P = 0.22). The rate of definite

stent thrombosis was reduced from 1.9% to 1.3% (P <0.01)andtotal

mortality from 5.9% to 4.5% (P < 0.001). Overall, there was no signifi-

cant difference in PLATO-defined major bleeding rates between the

clopidogrel and ticagrelor groups (11.2% vs. 11.6%, respectively; P =

0.43). Major bleeding unrelated to CABG was increased from 3.8% in

the clopidogrel group to 4.5% in the ticagrelor group (HR 1.19, 95%

CI 1.02–1.38; P = 0.03). Major bleeding related to CABG was similar

with ticagrelor and clopidogrel (7.4% vs. 7.9%, respectively; P = 0.32).

There was no difference in the overall rates of fatal haemorrhage

betweenthegroups(0.3%inbothgroups).Thesuperiorityofticagre-

lor over clopidogrel with respect to the primary study endpoint as

well as cardiovascular death or overall mortality was consistent across

management strategies, i.e. patients undergoing PCI, those medically

managed, and patients who underwent CABG.

No dedicated study exists assessing the value of early (i.e. before

coronary angiography) vs. delayed (i.e. after coronary angiography)

ticagrelor administration in patients with NSTE-ACS. The

Administration of Ticagrelor in the Cath Lab or in the Ambulance for

New ST Elevation Myocardial Infarction to Open the Coronary Artery

(ATLANTIC) study involved 1862 patients with STEMI <6-h duration

and compared pre-hospital (in the ambulance) vs. in-hospital (in the

catheterization laboratory) treatment with ticagrelor.

The co-

primary endpoints were the proportion of patients who did not have

>_70% resolution of ST-segment elevation before PCI and the propor-

tion of patients who did not have TIMI flow grade 3 in the infarct-

related artery at initial angiography. Secondary endpoints included the

rates of major adverse cardiovascular events (MACE) and definite

stent thrombosis at 30 days. The median time difference between the

two treatment strategies was 31 min. The two co-primary endpoints

did not differ significantly between the pre-hospital and in-hospital

groups. The rates of definite stent thrombosis were lower in the pre-

hospital group than in the in-hospital group (0% vs. 0.8%, P = 0.008 in

the first 24 h; 0.2% vs. 1.2%, P = 0.02 at 30 days). Rates of major bleed-

ing events were low and virtually identical in the two groups, regardless

of the bleeding definition used.

The value of ticagrelor beyond 12 months of therapy in patients

with prior ACS has been investigated in the Prevention of

Cardiovascular Events in Patients with Prior Heart Attack Using

Ticagrelor Compared to Placebo on a Background of

Aspirin–Thrombolysis in Myocardial Infarction (PEGASUS) trial,

which is described in Chapter 4.

P2Y

inhibitors in STEMI patients treated with lysis: Clopidogrel is the

only P2Y

inhibitor that has been properly investigated in patients

with STEMI undergoing initial treatment with thrombolysis.

31,32

Clopidogrel 300 mg loading dose has been investigated only in

patients <_75 years of age.

While not specifically investigating the

value of clopidogrel, in the STrategic Reperfusion Early After

Myocardial Infarction (STREAM) study, patients aged 75 or more

received clopidogrel treatment without loading dose (i.e. initiated at

75 mg q.d.) in association with half dose of lytic therapy.

Hence, the

administration of a clopidogrel loading dose in elderly patients

requires a patient-by-patient decision. While prasugrel

or ticagre-

lor

were allowed as per protocol in patients with prior treatment

with lysis in P2Y

inhibitor-naı¨vepatientsorthosewithpriorclopi-

dogrel administration, respectively, there are insufficient safety data to

recommend their concomitant use during or soon after thrombolysis.

Timing of initiation of P2Y

inhibitor: The evidence (and lack thereof)

on optimal timing for the initiation of P2Y

inhibitors has been

extensively discussed in previous guidelines

and reviewed else-

where.

35,36

A reasonable approach is to start treatment with a P2Y

inhibitor based on the timing with which the drug was investigated in

approval studies (i.e. start as soon as possible and deemed safe for

clopidogrel and ticagrelor or after the indication for PCI is established

based on coronary anatomy for prasugrel). The decision to withhold

early administration of P2Y

inhibitors may also depend on planned

222 ESC Guidelines

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use of cangrelor in the catheterization laboratory, which ensures

immediate inhibition of the target receptor in oral P2Y

inhibitor-

naı¨ve patients. Timing of administration of P2Y

inhibitors in patients

receiving cangrelor infusion at the time of PCI should be drug-spe-

cific.

While ticagrelor can be given any time before, during or at the

end of cangrelor infusion, it is recommended that clopidogrel or pra-

sugrel is given at the time of cangrelor infusion discontinuation (or

within 30 minutes before the end of infusion in the case of prasugrel

administration).

However, the comparative efficacy and safety of

routine early oral P2Y

inhibitor administration vs. the use of cangre-

lor in the catheterization laboratory in patients with ACS undergoing

invasive management deserves further investigation. If coronary anat-

omy is known or the probability of PCI is high (such as for STEMI

patients), there is evidence and general consensus that early adminis-

tration of oral P2Y

inhibitors outweighs any potential risks. On the

other hand, there are no convincing data that the benefits of early

administration of a P2Y

inhibitor outweigh the possible risks in sta-

ble CAD patients undergoing diagnostic angiography.

3.7 Measures to minimize bleeding while

on dual antiplatelet therapy

Bleeding events after successful PCI are independently associated

with increased mortality and morbidity and this association is likely

causal.

41,42

Therefore, every effort should be made to minimize

bleeding. Individualization of therapy is a key measure and includes

the identification of risk factors for bleeding, radial access site, dosing

of therapies, use of proton pump inhibitors (PPIs), and appropriate

selection of P2Y

inhibitors.

Vascular access site: The Minimizing Adverse Haemorrhagic Events

by Transradial Access Site and Systemic Implementation of angioX

(MATRIX) trial is the most contemporary and largest trial on access

site selection where 8404 ACS patients were randomly allocated to

radial or femoral access.

The first co-primary outcome of 30-day

MACE—defined as death, MI, or stroke—occurred in 8.8% of patients

with radial access and 10.3% of patients with femoral access [relative

risk (RR) 0.85, 95% CI 0.74–0.99; two-sided P = 0.031; formally non-

significant at the pre-specified a of 0.025]. The second co-primary

Recommendations on P2Y

inhibitor selection and timing

Recommendations Class

Level

In patients with ACS, ticagrelor (180 mg loading dose, 90 mg twice daily) on top of aspirin

is recommended, regardless

of initial treatment strategy, including patients pre-treated with clopidogrel (which should be discontinued when ticagre-

lor is commenced) unless there are contraindications.

I B

In patients with ACS undergoing PCI, prasugrel (60 mg loading dose, 10 mg daily dose) on top of aspirin is recom-

mended for P2Y

inhibitor-naı¨ve patients with NSTE-ACS or initially conservatively managed STEMI if indication for

PCI is established, or in STEMI patients undergoing immediate coronary catheterization

unless there is a high risk of

life-threatening bleeding or other contraindications.

I B

Pre-treatment with a P2Y

inhibitor is generally recommended in patients in whom coronary anatomy is known and

the decision to proceed to PCI is made as well as in patients with STEMI.

20,23,38

I A

In patients with NSTE-ACS undergoing invasive management, ticagrelor administration (180 mg loading dose, 90 mg

twice daily), or clopidogrel (600 mg loading dose, 75 mg daily dose) if ticagrelor is not an option, should be considered

as soon as the diagnosis is established.

IIa C

In patients with stable CAD, pre-treatment with clopidogrel may be considered if the probability of PCI is high.

IIb C

Clopidogrel (600 mg loading dose, 75 mg daily dose) on top of aspirin is recommended in stable CAD patients under-

going coronary stent implantation and in ACS patients who cannot receive ticagrelor or prasugrel, including those with

prior intracranial bleeding or indication for OAC.

20,23,39,40

I A

Clopidogrel (300 mg loading dose in patients aged <_75, 75 mg daily dose) is recommended on top of aspirin in STEMI

patients receiving thrombolysis.

31,32

I A

Ticagrelor or prasugrel on top of aspirin may be considered instead of clopidogrel in stable CAD patients undergoing

PCI, taking into account the ischaemic (e.g. high SYNTAX score, prior stent thrombosis, location and number of

implanted stents) and bleeding (e.g. according to PRECISE-DAPT score) risks.

IIb C

In NSTE-ACS patients in whom coronary anatomy is not known, it is not recommended to administer prasugrel.

III B

ACS = acute coronary syndrome; CAD = coronary artery disease; DAPT = dual antiplatelet therapy; NSTE-ACS = non-ST-elevation acute coronary syndrome; OAC = oral

anticoagulant; PCI = percutaneous coronary intervention; PRECISE-DAPT = PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual

Anti Platelet Therapy; STEMI = ST-elevation myocardial infarction; SYNTAX = Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery.

Class of recommendation.

Level of evidence.

Contraindications for ticagrelor: previous intracranial haemorrhage or ongoing bleeds. Contraindications for prasugrel: previous intracranial haemorrhage, previous ischaemic

stroke or transient ischaemic attack, or ongoing bleeds; prasugrel is not recommended for patients >_75 years of age or with a body weight <60 kg.

ESC Guidelines 223

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outcome of 30-day net adverse clinical events (NACE) [MACE or

non-CABG BARC (Bleeding Academic Research Consortium) major

bleeding] was experienced in 9.8% and 11.7% of patients, respectively

(RR 0.83, 95% CI 0.73–0.96; P = 0.009). Radial access was associated

with a lower risk of all-cause mortality (1.6% vs. 2.2%; RR 0.72, 95% CI

0.53–0.99; P = 0.045). Major BARC 3 or 5 bleeding was significantly

reduced in the radial group (1.6% vs. 2.3%; RR 0.67, 95% CI 0.49–0.92;

P = 0.013). Radial access was associated with significantly lower rates

of surgical access site repair or transfusion of blood products. An

updated meta-analysis including MATRIX found a significant reduction

in major bleeds; death, MI, or stroke; and in all-cause mortality associ-

ated with radial as compared to femoral access.

Aspirin dosing in patients treated with DAPT: Lower aspirin doses

(<_100 mg daily) have been consistently demonstrated to be associ-

ated with less major and total bleeding than higher doses, either

when used as monotherapy or when combined with the P2Y

inhibi-

tor clopidogrel.

45–52

This is because daily aspirin doses as low as

30–50 mg are able to completely inactivate the platelet cyclooxyge-

nase-1 enzyme and inhibit thromboxane production.

53,54

In addition,

the efficacy of ticagrelor may be decreased in patients treated with

higher aspirin doses (>_300 mg daily) vs. lower aspirin doses

(<_100 mg daily).

Although the molecular mechanism behind this

finding is not entirely clear, it reinforces the use of low dose aspirin.

The optimal range of aspirin dose in patients treated with DAPT that

provides maximal protection from ischaemic events and minimizes

bleeding risk appears to be 75–100 mg.

Platelet function testing, genetic testing, and switching of P2Y

inhibitors:

High and low platelet reactivity on P2Y

antagonist treatment pre-

dicts ischaemic and bleeding risks, respectively.

These data have led

to the rationale for individualized antiplatelet therapy based on plate-

let function monitoring to identify the patients out of the expected

range of platelet inhibition.

All randomized trials have failed to dem-

onstrate any benefit of platelet function monitoring to adjust

therapy.

58–60

The low-risk level of the study populations, the exclu-

sive use of clopidogrel, and the P2Y

reaction unit thresholds to

define the optimal window of P2Y

inhibition have been recognized

as the main limitations of these trials.

61–63

The Platelet Function Monitoring to Adjust Antiplatelet Therapy in

Elderly Patients Stented for an Acute Coronary Syndrome

(ANTARCTIC) trial has re-evaluated the concept of individualized

antiplatelet therapy by selecting only ACS patients at high risk of both

ischaemic and bleeding events (based on age >_75 years) and more

accurate thresholds in reflecting optimal P2Y

inhibition.

Clopidogrel was replaced by prasugrel using the recommended daily

dose of 5 mg for the elderly, with the possibility of adjustment up and

down according to individual response. Platelet function monitoring

performed 14 days after discharge and later if needed led to a change

of treatment in 45% of patients who were identified as being over-

treated or undertreated by measurement of the P2Y

inhibition

level; however, this strategy did not improve ischaemic or safety out-

comes.

The influence of genetic variants on the response to antipla-

telet agents, especially clopidogrel, has been well-established in

patients with ACS and planned PCI.

Rapidly-obtained genetic infor-

mation on the 2C19 genotype can help in reaching the optimal win-

dow of P2Y

inhibition according to the cytochrome P450 (CYP)

2C19 profile,

66,67

but no randomized trial has ever demonstrated any

clinical benefit of such an approach. Moreover, only 6–12% of the

variability in on-clopidogrel platelet reactivity can be explained by the

differences in genotype.

68,69

For these reasons, neither platelet function testing nor genetic testing

can be recommended for tailoring DAPT. It may be considered in spe-

cific situations (e.g. patients suffering from recurrent adverse events) if

the results may change the treatment strategy. This is the case for

patients undergoing CABG who are exposed to DAPT (see Chapter 5).

Proton pump inhibitors and DAPT: Gastrointestinal haemorrhage is

the most common serious bleeding complication from the use of

long-term antiplatelet therapy.

RCTs have shown that PPIs reduce

the rate of recurrent gastrointestinal bleeding in high-risk patients

receiving aspirin.

Similar data exist regarding the use of famotidine,

a histamine H

-receptor antagonist.

Clopidogrel requires metabolic transformation in the liver by CYP

isoenzymes (mainly CYP2C19) to elicit its antiplatelet effect. PPIs are

also metabolized by CYP enzymes, leading to a potential inhibition of

CYP2C19 (mainly omeprazole and esomeprazole) translating into

reduced metabolic activation of clopidogrel when taken together.

Pharmacodynamic studies demonstrated the reduction of

clopidogrel-induced antiplatelet effects when a PPI, mainly omepra-

zole, was concomitantly administered.

73–76

Based on drug–drug

interaction studies, omeprazole and esomeprazole would appear to

have the highest propensity for clinically relevant interactions, lanso-

prazole an intermediate probability, while pantoprazole and rabepra-

zole have the lowest.

However, importantly, no interaction

between concomitant use of PPIs and prasugrel or ticagrelor has

been observed.

Only observational studies suggested an increased risk of cardio-

vascular ischaemic events when PPI therapy was administered con-

comitantly with clopidogrel.

Conversely, randomized trials and

propensity score-matched studies did not support such

concerns.

76,79–81

The Clopidogrel and the Optimization of Gastrointestinal Events

Trial (COGENT) was a randomized, double-blind, double-dummy,

placebo-controlled, phase III study of the efficacy and safety of a

fixed-dose combination of clopidogrel (75 mg) and omeprazole

(20 mg), as compared with clopidogrel alone.

Patients were eligible

if they were 21 years of age or older and if the use of clopidogrel ther-

apy with concomitant aspirin was anticipated for at least the next

12 months, including patients presenting with an ACS or undergoing

placement of a coronary stent. Patients at high risk for gastrointestinal

bleeding were excluded (i.e. those in whom the need for a PPI, an H

receptor antagonist, sucralfate, or misoprostol was anticipated; with

pre-existing erosive oesophagitis or oesophageal or gastric variceal

disease or previous non-endoscopic gastric surgery; receipt of oral

anticoagulation therapy that could not be safely discontinued for the

duration of the study; or recent fibrinolytic therapy). Therefore, fol-

lowing previous evidence of benefit from a PPI or H

-receptor antag-

onist in high-risk patients treated with aspirin monotherapy, the

COGENT study included patients at low risk of gastrointestinal

bleeding undergoing DAPT, under the rationale that the risk of gas-

trointestinal bleeding is higher in patients taking aspirin and clopidog-

rel as compared to aspirin alone. This study was prematurely

stopped with a total of 3761 patients instead of the planned 5000 due

to financial reasons. The pre-specified primary gastrointestinal effi-

cacy endpoint was the time from randomization to the first occur-

rence of a composite of upper gastrointestinal clinical events, which

224 ESC Guidelines

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occurred in 1.1% of patients with omeprazole and 2.9% with placebo

at 180 days after randomization (HR 0.34, 95% CI 0.18–0.63; P <

0.001).

Furthermore, there was no significant increase in the risk of cardio-

vascular events with concomitant use of clopidogrel and omeprazole

(4.9%, 95% CI 3.4–6.4%, in the omeprazole group; and 5.7%, 95% CI

4.0–7.3%, in the placebo group; P = 0.98), a finding that was consistent

even in high-risk subgroups and for individual endpoints. The rate of

serious adverse events did not differ significantly between the two

groups (10.1% with omeprazole and 9.4% with placebo, P = 0.48), nor

did the rate of overall adverse events (41.3 and 42.8%, respectively; P =

0.33). Diarrhoea was reported in 3.0% of patients receiving omepra-

zole, as compared with 1.8% of those receiving placebo (P = 0.01).

There were no newly diagnosed cases of osteoporosis. One case of

peripheral neuropathy was reported in the placebo group.

No randomized data comparing use vs. non-use of PPI in patients

taking aspirin and prasugrel or ticagrelor exist. However, the risk of

gastrointestinal bleeding is higher with DAPT in the form of prasu-

grel

or ticagrelor

as compared to clopidogrel. The short- and

long-term safety profile of PPIs has been well-established.

Impaired

magnesium absorption with PPIs has been reported only from studies

in which patients had received a PPI for at least 1 year.

Magnesaemia monitoring is recommended at follow-up, especially

for longer than 1 year of therapy.

Type, dose of P2Y

inhibitor, and duration of treatment: Thetypeand

dose of P2Y

inhibitor are well-established according to the various set-

tings of CAD. Previous intracranial haemorrhage or ongoing bleeds are

common contraindications for prasugrel and ticagrelor, while prasugrel

should be given with caution in patients >_75 years of age or with a body

weight <60 kg. Patients with previous stroke or transient ischaemic

attack (TIA) may derive harm from prasugrel instead of clopidogrel.

Prior stroke is a marker of frailty and of subsequent risk of haemorrhagic

stroke, especially during the first year thereafter. Switching from prasu-

grel or ticagrelor to clopidogrel is a common practice, especially in cases

of minor bleeding or in patients with low platelet reactivity, a marker of

major bleeding risk.

56,84,85

There are no properly powered randomized

data on the long-term safety or efficacy of ‘switching’ patients treated

forweeksormonthswithaP2Y

inhibitor to a different P2Y

inhibi-

tor. Therefore, this practice is generally discouraged.

3.8 Switching between oral P2Y

inhibitors

Differences in the pharmacology of P2Y

receptor inhibitors with

regard to their binding site, half-life, and speed of onset and offset of

action are important factors that might lead to drug interactions

when switching from one agent to another.

The transition from clopidogrel to ticagrelor is the only switch

between P2Y

inhibitors that has been investigated in a trial pow-

ered for clinical endpoint, even if the study was not specifically

designed to assess the safety and efficacy of the transition from clo-

pidogrel to ticagrelor. In PLATO, nearly 50% of patients randomly

allocated to receive ticagrelor had been pre-treated with clopidog-

rel, mostly given as a 300–600 mg loading dose.

The efficacy and

safety of ticagrelor were not affected by previous clopidogrel expo-

sure.

On the other hand, the TRITON-TIMI 38 trial mandated

that previous exposure of patients to a P2Y

receptor inhibitor

Measures to minimize bleeding while on dual antiplatelet therapy

Recommendations Class

Level

Radial over femoral access is recommended for coronary angiography and PCI if performed by an expert radial operator.

43,44

I A

In patients treated with DAPT, a daily aspirin dose of 75 - 100 mg is recommended.

45–47,51,52

I A

A PPI in combination with DAPT

is recommended.

70,79,80,86,87

I B

Routine platelet function testing to adjust antiplatelet therapy before or after elective stenting is not recommended.

58–60

III A

DAPT = dual antiplatelet therapy; PCI = percutaneous coronary intervention; PPI proton pump inhibitor.

Class of recommendation.

Level of evidence.

While the evidence that a PPI does not increase the risk of cardiovascular events was generated with omeprazole, based on drug–drug interaction studies, omeprazole and

esomeprazole would appear to have the highest propensity for clinically relevant interactions, while pantoprazole and rabeprazole have the lowest.

Switching between oral P2Y

inhibitors

Recommendations Class

Level

In patients with ACS who were previously

exposed to clopidogrel, switching from clopi-

dogrel to ticagrelor is recommended early

after hospital admission at a loading dose of

180 mg irrespective of timing and loading

dose

of clopidogrel, unless contraindications

to ticagrelor exist.

I B

Additional switching between oral P2Y

inhibitors may be considered in cases of

side effects/drug intolerance according to

the proposed algorithms.

IIb C

ACS = acute coronary syndrome.

Class of recommendation.

Level of evidence.

Contraindications for ticagrelor: previous intracranial haemorrhage or ongoing

bleeds.

ESC Guidelines 225

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should be an exclusion criterion for study entry.

While registry data

provide reassuring information with respect to the safety profile of

switching from clopidogrel to prasugrel,

89–91

no randomized data exist

in the setting of studies powered for clinical endpoint. Similarly, all

other switching possibilities, including between prasugrel and tica-

grelor or from ticagrelor/prasugrel to clopidogrel, have not been

investigated with outcome data.

92–94

This practice is therefore dis-

couraged due to a lack of safety/efficacy data. As the need to switch

between P2Y

inhibitors may arise for clinical reasons (i.e. side

effects or drug intolerance), and registry data indicate that switch-

ing is not infrequent in practice, switching algorithms based on

pharmacodynamic studies are provided (Figure 2).

4. Dual antiplatelet therapy and

percutaneous coronary

intervention

An overview of all studies investigating the benefits and risks

of DAPT duration beyond 1 month, largely focusing on post-

PCI patients or those with prior ACS, is shown in Web addenda

Table S1 (A a nd B). An overview of recommendations endorsed

by these guidelines regarding DAPT duration after PCI, as well as

after CABG or in medically managed ACS patients, is provided in

Figure 3.

4.1 Dual antiplatelet therapy after

percutaneous coronary intervention for

stable coronary artery disease

DAPT is not indicated in purely medically managed patients (i.e. with-

out prior PCI) with stable CAD and no history of prior MI. The

Clopidogrel for High Atherothrombotic Risk and Ischemic

Stabilization, Management, and Avoidance (CHARISMA) study

included patients with stable vascular disease or at risk of athero-

thrombotic events, and showed that clopidogrel plus aspirin was not

significantly more effective than aspirin alone in reducing the rate of

MI, stroke, or death from cardiovascular causes.

After PCI with stent placement, DAPT is the standard of care. The

Intracoronary Stenting and Antithrombotic Regimen (ISAR) trial

and,

subsequently, other studies

96,97

established the 1-month course of

DAPT after bare-metal stent (BMS). An arbitrary 12-month or more

DAPT duration has been subsequently recommended based on expert

opinions after first generation DES, irrespective of clinical presentation.

No dedicated study exists focusing on stable CAD patients under-

going PCI and being exposed to different DAPT durations. Hence,

recommendations regarding stable CAD patients undergoing PCI

derive from subgroup analyses from pertinent RCTs (Figure 4).

98,99

While no RCTs investigating the use of ticagrelor or prasugrel

instead of clopidogrel in stable CAD patients undergoing PCI exist, this

treatment option may be considered in selected patients in whom the

use of clopidogrel is unsatisfactory based on prior clinical outcomes or

potentially associated with higher risk of ischaemic events that bleeding

recurrences.

Three- or 6- vs. at least 12-month DAPT duration: The Efficacy of

Xience/PromusVersusCyphertoReduceLateLossAfter

Stenting (EXCELLENT) trial compared a 6-month DAPT [acetyl-

salicylic acid (ASA) þ clopidogrel] duration with 1-year DAPT

after DES.

100

With 1443 patients randomized, the rates of target

vessel failure—defined as the composite of cardiac death, MI, or

ischaemia-driven target vessel revascularization—at 12 months

were 4.8% in the 6-month DAPT group and 4.3% in the 12-month

DAPT group (P = 0.001 for non-inferiority). There was a numeri-

cally lower risk of bleeding in the short DAPT arm (HR 0.50, 95%

CI 0.09–2.73). There was no signal of heterogeneity for the pri-

mary study endpoint with respect to clinical presentation (i.e. sta-

ble CAD, n = 699 patients vs. ACS, n = 744 patients). The

PROlonging Dual antiplatelet treatment after Grading stent-

induced intimal hYperplasia (PRODIGY) trial randomized 2013

patients

101

to 6 or 24 months of DAPT (ASA þ clopidogrel) and

to one of four stent types (a four-by-two factorial design), includ-

ing BMS and three different DES types. The 2-year incidence of all-

cause death, MI, and stroke or cerebrovascular accident was

10.1% with 24-month DAPT compared with 10.0% with 6-month

DAPT (P = 0.91). There was a lower risk of major bleeding with

shorter DAPT based on both the BARC (1.9% vs. 3.4%; HR 0.56,

95% CI 0.32–0.98; P = 0.037) or the TIMI scale (0.6% vs. 1.6%; HR

0.38, 95% CI 0.15–0.97; P = 0.041). After censoring events that

occurred after 12 months, while keeping the original randomiza-

tion design, the risk of TIMI major bleeding was 0.5% in the short-

term DAPT arm vs. 0.9% in the long-term DAPT arm (HR 0.56,

95% CI 0.19–1.66). In this trial, a total of 1465 (74.3%) patients

presented with ACS whereas 505 (25.7%) had stable CAD.

heterogeneity was noted with respect to the primary efficacy end-

point. There was a borderline quantitative interaction between

clinical presentations and bleeding outcomes (P values for interac-

tion=0.056forBARC2,3,or5;P = 0.091 for BARC 3 or 5), sug-

gesting a higher hazard of bleeding in the 24-month DAPT arm

when compared with the 6-month arm in the stable CAD patients,

which was not observed in the ACS patients.

Analysis of

NACE—consisting of death, MI, cerebrovascular accident, or

BARC 2, 3, or 5 bleeding—revealed significant harm from

extended DAPT in stable CAD patients (NACE in the 24-month

vs. 6-month DAPT arm: 13.3% vs. 5.6%; HR 2.5, 95% CI 1.35–4.69,

P = 0.004; NNT for harm = 13) and no benefit in the ACS popula-

tion (16.1% vs. 14.1%; HR 1.15, 95% CI 0.88–1.50; P = 0.29), with

positive quantitative interaction testing (P value for interaction =

0.024).

Patients with high CRUSADE (Can Rapid risk stratifica-

tion of Unstable angina patients Suppress ADverse outcomes with

Early implementation of the ACC/AHA Guidelines) bleeding risk

score treated with 24-month DAPT experienced a threefold

higher risk of major bleeding and a fivefold risk of red blood cell

transfusion as compared with 6-month therapy, without clear evi-

dence of benefit.

In 2014, three additional randomized studies were published

that compared 6 months of DAPT to 12 or 24 months of DAPT

(ASA þ clopidogrel): Is There a Life for DES After

Discontinuation of Clopidogrel (ITALIC),

102

Second Generation

Drug-Eluting Stent Implantation Followed by Six- Versus Twelve-

Month Dual Antiplatelet Therapy (SECURITY),

103

and

Intracoronary Stenting and Antithrombotic Regimen: Safety and

Efficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting

226 ESC Guidelines

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Stenting (ISAR-SAFE).

104

ISAR-SAFE was the largest of these three

studies, with 4005 randomized patients, and the only double-blind

investigation. It confirmed that a 12-month course of DAPT did

not afford any benefit over a 6-month course with respect to

ischaemic endpoints. Likewise, the net clinical benefit (composite

of death, MI, stent thrombosis, stroke, and TIMI major bleeding)

was neutral. At subgroup analysis, there was no signal of heteroge-

neity with respect to the primary study endpoint among the 2394

patients who presented with stable CAD as opposed to the 1601

patients with ACS.

104

Consistent results were shown in the

ITALIC and SECURITY trials. Two studies, Real Safety and Efficacy

of 3-Month Dual Antiplatelet Therapy Following Endeavor

Zotarolimus-Eluting Stent Implantation (RESET)

105

and

Optimized Duration of Clopidogrel Therapy Following Treatment

With the Zotarolimus-Eluting Stent in Real-World Clinical

Practice (OPTIMIZE),

106

investigated a 3-month duration of

DAPT (ASA þ clopidogrel). RESET randomized 2117 patients to

3- or 12-month duration of DAPT and did not show significant

Ticagrelor MD (90 mg b.i.d.)

24h after last Prasugrel dose

Figure 2 Algorithm for switching between oral P2Y

inhibitors in the acute and chronic setting. LD = loading dose; MD = maintenance dose.

Colour-coding refers to the ESC Classes of Recommendations (green = Class I; orange = Class IIb). The green arrow from clopidogrel to ticagrelor

highlights the only switching algorithm for which outcome data are available in patients with acute coronary syndrome. No outcome data (orange

arrows) are available for all other switching algorithms. Acute setting is considered as a switching occurring during hospitalization.

ESC Guidelines 227

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Figure 3 Algorithm for DAPT in patients with coronary artery disease. ACS = acute coronary syndrome, BMS = bare-metal stent; BRS = bioresorbable vascular scaffold; CABG = Coronary artery

bypass graft; DCB = drug-coated balloon; DES: drug-eluting stent; PCI = percutaneous coronary intervention; Stable CAD = stable coronary artery disease.

High bleeding risk is considered as an increased risk of spontaneous bleeding during DAPT (e.g. PRECISE-DAPT score >_25).

Colour-coding refers to the ESC Classes of Recommendations (green = Class I; yellow = Class IIa; orange = Class IIb).

Treatments presented within the same line are sorted in alphabetic order, no preferential recommendation unless clearly stated otherwise.

: After PCI with DCB 6 months. DAPT should be considered (Class IIa B).

: If patient presents with Stable CAD or, in case of ACS, is not eligible for a treatment with prasugrel or ticagrelor.

: If patient is not eligible for a treatment with prasugrel or ticagrelor.

: If patient is not eligible for a treatment with ticagrelor.

228 ESC Guidelines

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Figure 4 Algorithm for dual antiplatelet therapy (DAPT) in patients treated with percutaneous coronary intervention. ACS = acute coronary syn-

drome; BMS = bare-metal stent; BRS = bioresorbable vascular scaffold; CABG = coronary artery bypass graft surgery; DCB = drug-coated balloon;

DES: drug-eluting stent; PCI = percutaneous coronary intervention; Stable CAD = stable coronary artery disease.

High bleeding risk is considered as an increased risk of spontaneous bleeding during DAPT (e.g. PRECISE-DAPT score >_25).

Colour-coding refers to the ESC Classes of Recommendations (green = Class I; yellow = IIa; orange = Class IIb).

Treatments presented within the same line are sorted in alphabetic order, no preferential recommendation unless clearly stated

otherwise.

: After PCI with DCB 6 months. DAPT should be considered (Class IIa B).

: If patient presents with Stable CAD or, in case of ACS, is not eligible for a treatment with prasugrel or ticagrelor.

: If patient is not eligible for a treatment with prasugrel or ticagrelor.

: If patient is not eligible for a treatment with ticagrelor.

ESC Guidelines 229

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harm with the shortened period (composite rates of any death,

MI, or stent thrombosis 0.8% vs. 1.3%; P = 0.48). Similar results

were achieved in OPTIMIZE with 3119 patients randomized. In

this study, the 1-year incidence of MACE was 8.3% in the short-

term group and 7.4% in the long-term group (HR 1.12, 95% CI

0.87–1.45). Both studies mandated the use of the Endeavor

zotarolimus-eluting stent (ZES) in the 3-month DAPT arms, which

is no longer available on the market. It is not clear to what extent

the results of RESET and OPTIMIZE are applicable to other types

of DES.

Palmerini et al performed a meta-analysis addressing the outcome

of a <_6-month course of DAPT vs. a 1-year course after DES.

107

The

1-year course of therapy did not confer any advantage over the

shorter course of DAPT with respect to survival, stent thrombosis,

or MI, but it increased the risk of major bleeding substantially. Similar

results were obtained by other meta-analyses.

108,109

Twelve-month vs . >12-month DAPT duration: Following the pro-

posed landmark of 12 months as the standard DAPT duration

after DES, the DAPT trial investigated whether further extension

of DAPT might be beneficial.

110

The DAPT study enrolled patients

who, at 12 months after placement of a DES, were still on DAPT

and had not suffered an ischaemic or bleeding event. Patients

were randomly allocated to thienopyridine or placebo for another

18 months. Aspirin was maintained throughout the study period.

Thirty-month DAPT as compared with 12-month DAPT

reduced the rates of stent thrombosis (0.4% vs. 1.4%; P < 0.001)

and of major adverse cardiac and cerebrovascular events

(MACCE) (4.3% vs. 5.9%; P < 0.001). This included a substantial

reduction in the rate of MI (2.1% vs. 4.1%; P < 0.001); slightly

more than half of this benefit could be attributed to the preven-

tion of spontaneous MIs (see chapter 3.2). This ischaemic protec-

tion came at the cost of an increased risk of bleeding (GUSTO

moderate or severe bleeding 2.5% vs. 1.6%, P < 0.001) and an

increase in total mortality with borderline statistical significance

(see section 3.3).

Of 11 648 randomized patients within the DAPT trial (9961

treated with DES and 1687 with BMS), 30.7% presented with MI.

The excess of mortality observed within the 30-month DAPT arm

was entirely driven by fatalities, which occurred in patients without

prior MI (2.1% for continued thienopyridine group vs. 1.5% for pla-

cebo; HR 1.43, 95% CI 1.02–2.00; P = 0.04). Yet, the interaction

P value did not reach statistical significance (effect for MI vs. no MI

interaction P =0.13).

Three independent meta-analyses, which included 5045 patients

recruited within DES-Late coronary Arterial Thrombotic Events

(LATE)

111

and 1259 patients from the Assessment by a Double

Randomisation of a Conventional Antiplatelet Strategy Versus a

Monitoring-Guided Strategy for Drug-Eluting Stent Implantation and,

of Treatment Interruption Versus Continuation 1 Year After

Stenting-Interruption (ARCTIC-Interruption) trial,

112

provided

results consistent with a possible increase in mortality with pro-

longed DAPT as shown in the DAPT trial. A more recent meta-

analysis of 11 RCTs that enrolled 33 051 patients who received pre-

dominantly newer-generation DES also provided weak evidence of

an increased mortality rate with prolonged DAPT.

113

Thus, if DAPT is administered for a sufficient length of time after

placement of DES for stable CAD, a substantial benefit in terms of

secondary prevention and reduction of stent thrombosis emerges.

However, this benefit is counterbalanced by an increased risk of

bleeding and by a signal for increased mortality. Thus, systematic

extension of DAPT beyond six months is not justified for all patients

but should be based on the individual risk profile of the patient (see

section 3.5).

Impact of type of DES on duration of DAPT: The benefit of

extended periods of DAPT varies with stent type. However, there

are differences between first- and newer-generation DES. In

PRODIGY, only patients with the paclitaxel-eluting stent benefit-

ted from extended DAPT with a significant reduction of the risk of

stent thrombosis.

114

Likewise, in DAPT, the benefit of extended

DAPT was largest with patients with a paclitaxel-eluting stent and

the smallest with an everolimus-eluting stent.

110,115

There also was

a significant interaction between stent type and benefit of

extended DAPT with respect to MACCE.

110

With an everolimus-

eluting stent, the 1-year NNT for prevention of stent thrombosis

was 157, whereas the 1-year NNT for harm for moderate or

severe bleeding was 56.

115

In the meta-analysis by Giustino et al,

109

the reduction of stent thrombosis by extended DAPT was signifi-

cantly reduced with new-generation stents as compared with first-

generation DES, and statistical significance was lost within the

new-generation subset. No such interaction was found concerning

bleeding complications. Similar results were obtained in two other

meta-analyses (Sharma et al

116

and Palmerini et al

117

Bioresorbable stents and drug-coated balloons: No dedicated stud-

ies examining the optimal duration of DAPT after implantation of a

bioresorbable scaffold currently exist. In the largest randomized

clinical trial investigating the treatment of patients with a poly-lac-

tic acid-based bioresorbable scaffold, DAPT was recommended

for at least 12 months.

118

However, meta-analysis has shown evi-

dence of an approximately twofold higher rate of stent thrombosis

in comparison with conventional DES, especially in the first 30

days after implantation.

119

This provides a rationale for considering

more potent P2Y

inhibitors in these patients. In addition, some

concerns have been raised regarding late stent thrombosis beyond

1 year after implantation

120,121

and a longer duration of DAPT

therapy may be advocated, at least in patients at low bleeding risk.

No large-scale clinical trials are available concerning magnesium-

based bioresorbable scaffolds.

In patients treated with drug-coated balloons, dedicated clinical tri-

als investigating the optimal duration of DAPT are lacking. In patients

treated for in-stent restenosis, the largest randomized trials investi-

gating drug-coated balloon therapy have recommended a treatment

duration of between 3 - 12 months.

122–124

In addition, some small

clinical trials, as well as larger registries, including patients with stable

CAD undergoing drug-coated balloon angioplasty have recom-

mended DAPT duration of at least 1 month.

125

Plain old balloon angioplasty: no data on DAPT or DAPT duration

exist after plain old balloon angioplasty, which is currently

reserved for a small minority of patients in whom stent implanta-

tion is not feasible (e.g. small calibre vessel or extreme vessel tor-

tuosity) or desirable (e.g. to avoid DAPT in patients referred to

CABG). The institution of DAPT and its duration, if implemented,

should depend on clinical profile (ischaemic vs. bleeding risks)

and/or the reasons (e.g. planned surgery) for avoiding stent

implantation.

230 ESC Guidelines

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4.2 Dual antiplatelet therapy after

percutaneous coronary intervention for

acute coronary syndrome

DAPT with novel P2Y

inhibitors for 1 year after PCI for ACS: The evi-

dence supporting the value of the combination of aspirin and clopi-

dogrel in patients with ACS has been extensively reviewed in

previous guidelines (NSTE-ACS), and data supporting the superiority

of ticagrelor and prasugrel over clopidogrel in this setting are dis-

cussed in section 3.6.

Although both prasugrel and ticagrelor significantly increase the

risk of TIMI major non-CABG related bleeds, the risk–benefit ratios

were favourable with NNT for benefit of 46 and 53, respectively, and

NNT for harm of 167 for both agents. These data established the 1-

year course of DAPT, preferably with prasugrel or ticagrelor, for

patients undergoing PCI for ACS, unless there are contraindications

(Figure 4).

Mounting evidence for secondary prevention by intensified antiplatelet

therapy: In patients presenting with ACS, the cardiovascular risk

remains substantially elevated beyond the first year, even if successful

revascularization has been achieved. In this setting, intensified antipla-

telet therapy on top of aspirin has been shown to be an effective

therapeutic strategy to prevent recurrent ischaemic events.

However, the risk–benefit ratios seem less favourable than those

observed in studies assessing <_1-year DAPT duration. Relevant infor-

mation has been provided by the prior MI patient subsets included in

the CHARISMA

135

(n = 3846) and DAPT

(n = 3576) trials, which

mainly compared clopidogrel with placebo on top of aspirin; by the

subset of patients who underwent coronary angiography within the

TRILOGY

136

trial, which compared prasugrel with clopidogrel; and

by the patients with prior MI within the Thrombin Receptor

Antagonist in Secondary Prevention of Atherothrombotic Ischemic

Events (TRA 2



P-TIMI 50)

137

(n = 17 779 ) trial, which compared

vorapaxar with placebo. Taken separately, these trial results are diffi-

cult to interpret because they are based on subgroup analyses.

Moreover, CHARISMA and TRILOGY had a neutral main outcome

and the main results of TRA 2



P-TIMI 50 showed an unfavourable

risk–benefit ratio. Therefore, a dedicated trial on prolonged DAPT

for secondary prevention after ACS was needed. The PEGASUS trial

filled this gap.

DAPT with ticagrelor for secondary prevention after MI: PEGASUS

recruited 21 162 patients with spontaneous MI 1–3 years before

enrolment, who were at >_50 years old and had at least one additional

high-risk feature: age >_65 years, diabetes mellitus, a second spontane-

ous MI, multivessel CAD, or chronic renal dysfunction.

The patients

were randomly assigned to ticagrelor 90 mg b.i.d., ticagrelor 60 mg

b.i.d., or placebo. All the patients received low-dose aspirin. Of the

patients included in PEGASUS, 53% were enrolled after a STEMI and

83% were previously treated by PCI. The primary efficacy endpoint

was the composite of cardiovascular death, MI, or stroke at 3 years

and was 7.85% in the 90 mg arm, 7.77% in the 60 mg arm, and 9.04%

in the placebo arm (P = 0.008 and P = 0.004 for the higher and lower

doses, respectively, vs. placebo).

There was a consistent reduction

in all components of the primary endpoint with ticagrelor vs. placebo,

which reached statistical significance for MI with both doses of tica-

grelor and for stroke with the lower dose. There was also a trend for

a reduction in cardiovascular mortality. Due to a non-significant yet

numerical increase in non-cardiovascular deaths in the two ticagrelor

arms, the outcome was neutral with respect to all-cause death. The

primary safety endpoint of TIMI major bleeding was observed more

frequently with ticagrelor (2.60% with 90 mg and 2.30% with 60 mg)

than with placebo (1.06%) (P < 0.001 for each dose vs. placebo). The

NNT for benefit for the primary endpoint was 250 for the 90 mg

Dual antiplatelet therapy duration and related stent

choices in patients with stable coronary artery disease

treated with percutaneous coronary intervention

Recommendations Class

Level

In patients with stable CAD treated with

coronary stent implantation, DAPT consist-

ing of clopidogrel in addition to aspirin is

generally recommended

for 6 months, irre-

spective of the stent type.

100,101,104,126–130

I A

Irrespective of the intended DAPT duration,

DES

is the preferred treatment option.

129–132

I A

In patients with stable CAD considered at high

bleeding risk (e.g. PRECISE-DAPT >_25), DAPT

for 3 months

should be considered.

105,106

IIa B

In patients with stable CAD treated with

drug-coated balloon, DAPT for 6 months

should be considered.

122,124,133

IIa B

In patients with stable CAD treated with

bioresorbable vascular scaffolds, DAPT for

at least 12 months should be considered.

IIa C

In patients with stable CAD who have toler-

ated DAPT without a bleeding complication

and who are at low bleeding but high throm-

botic risk, continuation of DAPT with clopi-

dogrel for >6 months and <_30 months may

be considered.

26,107–109

IIb A

In patients with stable CAD in whom 3-

month DAPT poses safety concerns, DAPT

for 1 month

may be considered.

IIb C

BMS = bare-metal stent; CAD = coronary artery disease; DAPT = dual antiplate-

let therapy; DES = drug-eluting stent; MI = myocardial infarction; PRECISE-DAPT

= PREdicting bleeding Complications In patients undergoing Stent implantation

and subsEquent Dual Anti Platelet Therapy.

Class of recommendation.

Level of evidence.

These recommendations refer to stents that are supported by large-scale

randomized trials with clinical endpoint evaluation leading to unconditional CE

mark, as detailed in Byrne et al.

134

The evidence supporting this recommendation comes from two studies where

zotarolimus-eluting Endeavour sprint stent has been investigated in conjunction

with a 3-month DAPT regimen.

1-month DAPT following implantation of zotarolimus-eluting Endeavour sprint stent

or Biofreedom drug-coated stent reduced risks of re-intervention, myocardial infarc-

tion and inconsistently of stent thrombosis compared to bare-metal stent under simi-

lar DAPT duration.

129,130

It is unclear if this evidence applies to other contemporary

DES.

ESC Guidelines 231

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dose and 238 for the 60 mg dose; the corresponding NNT for harm

was 244 and 322, respectively, with the two ticagrelor doses.

With the 90 mg dose, the absolute benefit in terms of the primary

efficacy endpoint was in the same order as the absolute harm in

terms of the primary safety endpoint, and with 60 mg the absolute

benefit was only marginally larger than the absolute harm. However,

the relevance of the various endpoints to the patient’s overall well-

being may differ and are, therefore, difficult to weigh against one

another. The impact of MI and bleeding on mortality was comparable

in previous studies.

11,138

A post hoc analysis from the Thrombin

Receptor Antagonist for Clinical Event Reduction in Acute Coronary

Syndrome (TRACER) trial suggested that while bleeding according to

BARC 2 and 3a criteria was less prognostic for death than MI, the risk

of mortality was equivalent between BARC 3b bleeding and MI, and

was higher following BARC 3c bleeding. Moreover, at variance with

previous analyses, both MI and bleeding impacted mortality with simi-

lar time dependency.

In view of these consistent findings through-

out multiple independent studies, both the efficacy and the safety

endpoints deserve attention, as both most likely similarly impact

mortality. With this background, the narrow risk–benefit ratio cau-

tions against the universal long-term administration of ticagrelor for

secondary prevention after MI, and calls for individualized treatment

decisions based on ischaemic and haemorrhagic risk.

To this end, patients who continued their thienopyridine treat-

ment without (a major) interruption (<_30 days) derived a larger

benefit from extended ticagrelor intake than patients who inter-

rupted their thienopyridine treatment for longer periods of

time.

139

Depending on the actual discontinuation time frame of

previous thienopyridine therapy, the HRs (95% CI) of the primary

endpoint for ticagrelor (pooled doses) vs. placebo were 0.73

(0.61–0.87) for those who continued within 30 days, 0.86

(0.71–1.04) for those who interrupted for 30 days to 1 year, and

1.01 (0.80–1.27) for those who interrupted for more than 1 year

(P trend for interaction < 0.001).

139

There was no significant inter-

action of timing with the effect of ticagrelor on bleeding risk. These

findings suggest that patients who can continue their initial thieno-

pyridine treatment are those deriving relatively greater benefit

from DAPT continuation with ticagrelor. Nevertheless, even in

this patient subset, the absolute increase in TIMI major bleeding

associated with extended ticagrelor was similar in magnitude as

compared to the absolute decrease in the composite ischaemic

endpoint (i.e. 1.9 percentage point difference for both the safety

and the efficacy endpoints).

139

Patients with lower-extremities artery disease (LEAD), who are

known to be at greater ischaemic risk, also derived heightened bene-

fit from extended ticagrelor.

140

In these patients, the absolute

decreases in the primary efficacy endpoint achieved by ticagrelor vs.

placebo were 3.0% for the 90 mg dose and 5.2% for the 60 mg dose,

whereas the increases in TIMI major bleeding were only 0.22% and

0.02%, respectively. In addition, ticagrelor was significantly associated

with fewer events related to LEAD (i.e. acute limb ischaemia and

peripheral revascularization procedures).

DAPT with thienopyridines (clopidogrel or prasugrel) for secondary pre-

vention after MI: In the DAPT trial, 3567 patients had initially pre-

sented with MI.

A non-prespecified analysis of these patients

investigated whether the benefits and risks of extended vs. standard

duration of DAPT was similar among patients with or without MI.

The active comparator was prasugrel in one-third of the patients

with MI and clopidogrel in two-thirds of the patients.

In patients with MI, extended DAPT as compared with aspirin

alone reduced stent thrombosis significantly (0.5% vs. 1.9%; P <

0.001). There also was a significant reduction of MACCE by extended

DAPT (3.9% vs. 6.8%; P < 0.001). This included a major reduction in

the rate of recurrent MI (2.2% vs. 5.2%; P < 0.001). On the other side,

GUSTO moderate or severe bleeding was significantly increased by

extended DAPT (1.9% vs. 0.8%, P = 0.005). Contrary to the main

study, all-cause mortality was similar in the extended DAPT group as

compared with the placebo group (1.4% vs. 1.6%; P = 0.61), even if

formal interaction testing was inconclusive.

A meta-analysis on the effect of extended DAPT in patients

with previous MI comprising PEGASUS and MI subgroups of stud-

ies with thienopyridines—CHARISMA, PRODIGY, and DES-

LATE with clopidogrel as well as ARCTIC-Interruption and DAPT

with clopidogrel or prasugrel—has been recently published.

141

Extended DAPT decreased the risk of MACCE compared with

aspirin alone (6.4% vs. 7.5%; P = 0.001). There was a consistent sig-

nificant reduction in each component of the primary endpoint (RR

0.85, 95% CI 0.74–0.98 for cardiovascular death; RR 0.70, 95% CI

0.55–0.88 for MI; RR 0.81, 95% CI 0.68–0.97 for stroke). This ben-

efit was achieved at the cost of a significantly increased risk of

major bleeding (1.85% vs. 1.09%; P = 0.004). Although the reduc-

tion in cardiovascular mortality associated with prolonged DAPT

was significant, the absolute risk reduction was small (0.3%). In

addition, there was no difference in all-cause mortality (4.0% in

the extended DAPT group and 4.2% in the aspirin alone group).

No significant difference between study heterogeneity was identi-

fied across the appraised endpoints. This may suggest a consistent

class effect among the three P2Y

inhibitors (clopidogrel, ticagre-

lor, or prasugrel). However, caution should be used in interpreting

this finding, taking into account that the PEGASUS study alone

contributed >_60% to pooled endpoint estimates and that

PEGASUS was the only trial included in its totality (and as such the

only properly powered study for post-MI patients), whereas post

hoc subgroups of patients recruited in the other four investigations

were pooled. In addition, when the overall included populations

of the four available studies assessing DAPT for >1 year vs. 12-

month therapy are pooled, an extended treatment with ticagrelor,

as compared to a similar strategy with thienopyridines, exerted a

more favourable effect on all-cause mortality due to a trend

towards reduction of cardiovascular death and a null effect on

non-cardiovascular death.

142

Finally, PEGASUS was the only trial

that allowed patients who had stopped DAPT months or years

before to randomly restart therapy; this likely resulted in relatively

lower efficacy endpoint estimates as compared to other studies

testing duration of thienopyridines where treatment was either

permanently stopped or continued without treatment interrup-

tions in between. Therefore, it is reasonable to favour ticagrelor

60 mg b.i.d. as the agent of choice for prolonging DAPT beyond

12 months in stabilized post-MI patients at low bleeding risk, and

to reserve the use of clopidogrel (or prasugrel, the least investi-

gated agent in this setting) as the alternative choice if ticagrelor

therapy is not tolerated or feasible.

232 ESC Guidelines

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Shortening of DAPT duration in patients at high bleeding risk: There is

no dedicated RCT assessing the optimal DAPT duration in patients at

high bleeding risk. Moreover, many, if not all, available DAPT studies

formally excluded these patients from inclusion. The Zotarolimus-

eluting Endeavor sprint stent in Uncertain DES Candidates (ZEUS)

and the Prospective randomized comparison of the BioFreedom biol-

imus A9 drug-coated stent versus the gazelle BMS in patients at high

bleeding risk (LEADERS-FREE) studies recruited a selected high

bleeding risk population and randomized them to BMS or drug-

coated stent under a protocol-mandated DAPT duration of

1 month.

129,130

Both studies, as discussed in section 2.4, proved the

superiority of the investigated DES technologies as compared to BMS

despite a similarly short duration of DAPT. The trade-off between

bleeding prevention and ischaemic protection of prolonging DAPT

beyond 1 month in this patient subset remains unclear.

As discussed in section 4.1, two studies compared 3- vs. 12-month

DAPT duration after DES. Patients were not selected based on high

bleeding risk criteria and both studies included only a minority of

patients presenting with acute MI (14.3 and 5.4% in the RESET and

OPTIMIZE trials, respectively).

105,106

After an ACS, high bleeding risk status poses even greater

challenges with respect to the choice of DAPT duration. The

risks of shortening DAPT below 1 year have been addressed by

an individual patient data meta-analysis.

143

This meta-analysis

comprised six trials comparing three- or six-month DAPT with

12-month DAPT including 11 473 patients, 4758 of whom had

ACS. In patients with ACS, shortening DAPT to <_ 6 months was

associated with an estimated increase in the risk of MI or defi-

nite/probable stent thrombosis from 1.7% to 2.4% compared

with 1-year DAPT. Although this increase did not reach statisti-

cal significance (HR 1.48, 95% CI 0.98–2.22; P = 0.059), it has

to be kept in mind that the power of this analysis was limited

since the number of patients with ACS included was roughly

only one-third or one-fourth of that in TRITON or PLATO,

which established the superiority of intensified antiplatelet ther-

apy over conventional 1-year DAPT with clopidogrel. Despite

this limitation, it is probably fair to conclude that the ischaemic

risk of shortening DAPT to 6 months after PCI in ACS is low,

although not negligible. In this respect, it is also reassuring that

there was no signal with respect to cardiac or all-cause death

(HR 0.75, 95% CI 0.45–1.27 and HR 0.85, 95% CI 0.58–1.26,

respectively). Only when DAPT duration was reduced to

3 months did the risk of MI and definite/probable stent throm-

bosis increase substantially (HR 2.08, 95% CI 1.10–3.93).

In summary, currently available evidence suggests considering

discontinuation of P2Y

inhibitor therapy after 6 months, when

the risk of bleeding is high.

4.3 Gaps in the evidence

With a marginal overall benefit-to-risk ratio of extended DAPT beyond

1 year after DES placement, tools to identify ideal candidates for long-

term or even indefinite DAPT duration are critically needed. The DAPT

score

as well as the subgroup analyses of PEGASUS

139,140,144,145

are

important steps forward, but prospective validation in contemporary

cohorts of newer-generation DES patients is needed.

Dual antiplatelet therapy duration in patients with acute coronary syndrome treated with percutaneous coronary

intervention

Recommendations Class

Level

In patients with ACS treated with coronary stent implantation, DAPT with a P2Y

inhibitor on top of aspirin is rec-

ommended for 12 months unless there are contraindications such as excessive risk of bleeding (e.g. PRECISE-DAPT

>_25).

20,23,40

I A

In patients with ACS and stent implantation who are at high risk of bleeding (e.g. PRECISE-DAPT >_25), discontinua-

tion of P2Y

inhibitor therapy after 6 months should be considered.

13,18,143

IIa B

In patients with ACS treated with bioresorbable vascular scaffolds, DAPT for at least 12 months should be

considered.

IIa C

In patients with ACS who have tolerated DAPT without a bleeding complication, continuation of DAPT for longer

than 12 months may be considered.

26,139

IIb A

In patients with MI and high ischaemic risk

who have tolerated DAPT without a bleeding complication, ticagrelor

60 mg b.i.d. for longer than 12 months on top of aspirin may be preferred over clopidogrel or prasugrel.

29,115,142

IIb B

ACS = acute coronary syndrome; b.i.d.=bis in die; DAPT = dual antiplatelet therapy. MI = myocardial infarction; PRECISE-DAPT = PREdicting bleeding Complications In

patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy.

Class of recommendation.

Level of evidence.

Deﬁned as >_ 50 years of age, and one or more of the following additional high-risk features: age of 65 years or older, diabetes mellitus requiring medication, a second prior

spontaneous myocardial infarction, multivessel coronary artery disease, or chronic renal dysfunction, deﬁned as an estimated creatinine clearance < 60 mL/min.

These recommendations refer to stents that are supported by large-scale randomized trials with clinical endpoint evaluation leading to unconditional CE mark, as detailed in

Byrne et al.

134

ESC Guidelines 233

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The optimal level of platelet inhibition during the various stages of

CAD remains an open question. The risk of ischaemic complication is

highest immediately after PCI and then gradually declines. The same

is true for patients managed for ACS, although the risk remains ele-

vated above that of patients who never experienced an acute exacer-

bation for years. Thus, it is intuitive that during the chronic phase

after stabilization the level of platelet inhibition may be reduced as

compared with the acute phase. Until recently, there were only lim-

ited data addressing this issue from beyond the periprocedural phase

to 1 year. By now, two studies addressing such a step-down concept

have finished recruitment: Testing Responsiveness to Platelet

Inhibition on Chronic Antiplatelet Treatment For Acute Coronary

Syndromes Trial (TROPICAL-ACS) (NCT01959451) with a step-

down from prasugrel to clopidogrel after the peri-interventional

phase in acute MI; and GLOBAL-LEADERS (NCT01813435)

146

with

a step-down from DAPT to single antiplatelet therapy with ticagrelor

beyond the first month after PCI in an all-comers cohort with DES.

The risks and benefits of shortening DAPT to 3 months or even

shorter is another area with limited evidence. There are only two

randomized studies with a total of 5236 patients.

105,106

Both studies

used the first-generation ZES that, due to its limited efficacy in sup-

pressing neointima formation, has been largely replaced by a newer

generation. Thus, in most cases with high bleeding risk, the decision

to shorten DAPT below 6 months needs to rely on circumstantial

evidence suggesting comparable safety of different stent types.

As outlined in section 4.1, there are no dedicated studies on the opti-

mal duration of DAPT after the application of drug-eluting balloons or

after implantation of a bioresorbable scaffold. It is also unclear whether,

early after placement of a bioresorbable stent, patients may benefit

from the more potent P2Y

inhibition achieved by prasugrel or ticagre-

lor as compared with the current practice of clopidogrel administration.

5. Dual antiplatelet therapy and

cardiac surgery

5.1 Dual antiplatelet therapy in patients

treated with coronary artery bypass

surgery for stable coronary artery

disease

DAPT in ACS patients significantly reduces the risk of thrombotic com-

plications but increases the risk for both spontaneous and surgical

bleeding complications.

20,23,40

The bleeding risk as well as the ischaemic

benefit are further increased if ticagrelor or prasugrel are used instead

of clopidogrel.

20,23

Unlike for ACS, there is currently no evidence of a

survival benefit or a reduction of thromboembolic complications with

DAPT in patients with stable CAD undergoing CABG. However, there

is limited evidence suggesting that the use of DAPT in patients with sta-

ble CAD mitigates the risk of vein (but not arterial) graft occlusions.

5.2 Dual antiplatelet therapy in patients

treated with coronary artery bypass

surgery for acute coronary syndrome

Background: DAPT, as compared to aspirin monotherapy, has been pro-

ven to be beneficial in reducing ischaemic risk in ACS patients (Figure 5).

However, there is limited evidence in patients undergoing CABG as no

dedicated study exists. In the Clopidogrel in Unstable Angina to Prevent

Recurrent Events (CURE) trial, the outcome in the CABG

Figure 5 Algorithm for dual antiplatelet therapy (DAPT) in

patients with acute coronary syndrome undergoing coronary artery

bypass grafting. High bleeding risk is considered as an increased risk of

spontaneous bleeding during DAPT (e.g. PRECISE-DAPT score >_25).

Colour-coding refers to the ESC Classes of Recommendations

(green = Class I; yellow = IIa; orange = Class IIb). Treatments pre-

sented within the same line are sorted in alphabetic order, no prefer-

ential recommendation unless clearly stated otherwise.

1: if patient is not eligible for a treatment with prasugrel or

ticagrelor.

234 ESC Guidelines

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subpopulation was consistent with the overall results of the study.

147

Further support has been presented in two meta-analyses.

148,149

In the

CABG substudies of the TRITON-TIMI 38 and the PLATO trials where,

respectively, prasugrel and ticagrelor were tested against clopidogrel in

combinationwithASA,bothnewerP2Y

inhibitors were more effec-

tive than clopidogrel in preventing fatal outcomes, with a higher risk for

bleeding in the former but not the latter trial.

150,151

Continuation of DAPT until CABG increases the risk of excessive

perioperative bleeding, transfusions, and re-exploration for bleeding

as shown in RCTs,

147,150,151

observational studies,

152,153

and meta-

analyses.

154,155

Therefore, it is recommended that the P2Y

inhibitor

be discontinued whenever possible before elective CABG.

156,157

Alternatively, elective operations may be postponed until the DAPT

treatment period is completed. In urgent cases, most often patients

with ACS, the risk of thrombotic episodes (stent thrombosis or MI)

while waiting for the effect of the P2Y

inhibitor to cease must be

weighed against the risk of perioperative bleeding complications. In

extreme high-risk patients, e.g. those with recent DES implantation,

bridging therapy with cangrelor or a glycoprotein IIb/IIIa blocker may

be considered.

156,157

P2Y

inhibitors: The safe discontinuation interval varies between

the different P2Y

inhibitors due to variations in platelet inhibitory

effect and pharmacodynamic and pharmacokinetic properties.

158

For

clopidogrel, it was shown in the CABG substudy of the CURE trial

that discontinuation >_5 days before CABG did not increase the risk

of bleeding complications.

147

For prasugrel, a longer time interval

(7 days) is recommended due to the longer offset time compared to

clopidogrel

158

and the high incidence of CABG-related bleeding com-

plications reported in the CABG substudy of the TRITON-TIMI

38 trial.

151

In CABG patients treated pre-operatively with ticagrelor,

5 days of discontinuation was initially recommended. This recom-

mendation was based on pharmacokinetic studies and clinical data

from patients with stable CAD.

159

However, recent data from large

observational studies in CABG patients challenge this recommenda-

tion.

152,153,160

In a Swedish nationwide study, CABG-related bleeding

complications in patients treated with ticagrelor or clopidogrel were

thoroughly investigated with respect to timing of P2Y

inhibitor dis-

continuation.

152

When either drug was discontinued according to

the instructions for use (>120 h before surgery), there was no significant

difference in the incidence of major bleeding complications between

ticagrelor- and clopidogrel-treated patients (9% vs. 12%; unadjusted OR

0.72, 95% CI 0.51–1.02; P = 0.065). Within the ticagrelor group, there

was no significant difference in major bleeding complications between

discontinuation 72–120 h or > 120 h before surgery (OR 0.93, 95% CI

0.53–1.64; P = 0.80), whereas discontinuation 0–72 h before surgery

was associated with a significantly higher rate of major bleeding com-

pared with both 72–120 h (OR 5.17, 95% CI 2.89–9.27; P < 0.0001)

and >120 h (OR 4.81, 95% CI 3.34–6.95; P < 0.0001). In contrast,

clopidogrel-treated patients had a higher incidence of major bleeding

complications when discontinued 72–120 h compared with >120 h

before surgery (OR 1.71, 95% CI 1.04–2.79; P = 0.033). Likewise, in the

clopidogrel group, discontinuation 0–72 h before surgery was associ-

ated with an increased incidence of major bleeding compared with

72–120 h (OR 1.67, 95% CI 1.02–2.73; P = 0.042) and >120 h (OR

2.85, 95% CI 1.98–4.10; P < 0.0001) (Web Figure 2,seeWeb

Addenda).

152

Further support for using 3 days as the discontinuation

period in ticagrelor-treated patients comes from the PLATO trial,

where a discontinuation period of 24 - 72 h was recommended. In a sin-

gle institution Dutch registry encompassing 705 consecutive patients

who underwent isolated on-pump CABG, ticagrelor discontinuation

>72 h and clopidogrel discontinuation >120 h before surgery were not

associated with an increased risk of bleeding-related complications.

153

Further evidence comes from a prospective, multicentre clinical

trial performed at 15 European centres, where discontinuation of

ticagrelor >2 days before surgery was not associated with increased

bleeding.

160

It is unlikely that the optimal discontinuation period for any of

the P2Y

inhibitors will ever be tested in an RCT. As mentioned

above, current guidelines recommend DAPT in all patients with

ACS, independent of revascularization strategy.

34,161

This applies

to patients undergoing CABG and other cardiac surgical proce-

dures as well. Furthermore, the effect of DAPT or single antiplate-

let therapy after CABG has been compared in two meta-analyses

based on RCTs

148

or a combination of RCTs and observational

studies.

149

In the meta-analysis based on RCTs only (which

included 3717 ACS patients),

148

there were no differences in all-

cause mortality in ASA þ clopidogrel vs. ASA only. Conversely,

all-cause mortality was significantly lower in ASA þ ticagrelor and

ASA þ prasugrel vs. ASA þ clopidogrel RCTs (RR 0.49, 95 % CI

0.33–0.71; P = 0.0002). There were no significant differences in

occurrence of MIs, strokes, composite outcomes, or major bleed-

ing (RR 1.31, 95 % CI 0.81–2.10, P = 0.27). The meta-analysis

based on both RCTs and observational studies

149

included only

DAPT patients treated with clopidogrel. In this analysis, in-

hospital or 30-day mortality was lower with ASA þ clopidogrel

compared to ASA alone (RR 0.38, 95% CI 0.26–0.57; P < 0.001),

while the risk of angina or perioperative MI was comparable (RR

0.60, 95% CI 0.31–1.14; P = 0.12). Long-term mortality was not

reported. Patients treated with ASA þ clopidogrel demonstrated a

trend towards a higher incidence of major bleeding episodes as com-

pared to patients treated with ASA alone (RR 1.17, 95% CI 1.00–1.37;

P = 0.05). In both meta-analyses, there was large heterogeneity

between the included studies regarding study drug (clopidogrel/prasu-

grel/ticagrelor), study design, patient inclusion (ACS vs. stable CAD,

on-pump vs. off-pump surgery), study quality, and duration of follow-

up. The positive effect on survival appears to be more pronounced in

ACS patients and in patients treated with the second-generation P2Y

inhibitors ticagrelor and prasugrel. However, re-institution of DAPT

after CABG may also slightly increase the risk of bleeding complica-

tions. Thus, it is recommended that DAPT is re-started as soon as it is

considered safe after CABG in ACS patients, with the exception of

those on anticoagulation. There is currently no scientific support for

triple antithrombotic treatment after CABG. Resuming DAPT early

after CABG is most likely of special importance in patients with recent

stent implantation, although strong evidence is lacking. The optimal

timing of resuming DAPT remains unclear, but 24 - 96 h after the oper-

ation in patients without recent stentimplantationappears reasonable.

One reason for not starting DAPT immediately after the operation is

the considerable risk (30%) of atrial fibrillation (AF) during the first

post-operative days, which requires oral anticoagulation.

162

Acetylsalicylic acid: A recent meta-analysis comparing pre-operative

ASA administration vs. no treatment or placebo in CABG patients

included 13 trials with a total of 2399 patients.

163

The meta-analysis

showed that treatment with ASA reduced the risk of perioperative

ESC Guidelines 235

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MI (OR 0.56, 95% CI 0.33–0.96) but not the mortality risk (OR 1.16,

95% CI 0.42–3.22), while post-operative bleeding, red blood cell

transfusions, and surgical re-explorations increased with ASA. The

authors pointed out that included studies had low methodological

quality. The recent Aspirin and Tranexamic Acid for Coronary

Artery Surgery (ATACAS) trial compared administration of ASA

(100 mg) on the day of surgery vs. placebo in CABG patients.

164

The

study showed no significant effect of ASA treatment on perioperative

bleeding. On the other hand, ASA treatment did not reduce the inci-

dence of thrombotic events. It should be pointed out that the study

did not directly compare discontinuation vs. no discontinuation, since

the included patients were only eligible for the trial if they were not

using ASA pre-operatively or had stopped ASA at least 4 days before

surgery. Thus, the ATACAS study does not directly apply to the

ACS-CABG population and does not change current recommenda-

tions of maintaining ASA treatment during the perioperative period.

In a case-control study on 8641 CABG patients, those pre-treated

with ASA were less likely to experience in-hospital mortality in uni-

variate (OR 0.73, 95% CI 0.54–0.97) and multivariate (OR 0.55, 95%

CI 0.31–0.98) analysis relative to those not exposed to ASA.

165

significant difference was seen in the amount of chest tube drainage,

transfusion of blood products, or need for re-exploration for bleed-

ing, between patients who were or were not exposed to ASA pre-

operatively.

Taken together, the evidence indicates that continuation of ASA

until cardiac surgery is associated with a moderately increased risk of

bleeding complications and a significant reduction in the risk of perio-

perative MI. If bleeding occurs during surgery, platelet transfusion has

been shown to effectively counteract ASA effects.

166–168

This finding

further supports the possibility of continuing ASA throughout the

perisurgical period as ASA allows direct antiplatelet effect reversal if

clinically indicated. The increased risk of bleeding complications if

ASA and other antithrombotic drugs are not discontinued should be

weighed against the potentially increased risk of thrombotic compli-

cations during the pre-operative cessation period.

Platelet function testing: Besides the variance in platelet inhibitory

effects between different P2Y

inhibitors, there is also a large individ-

ual variation in the magnitude and duration of the antiplatelet

effect.

20,159,169–171

Because of the individual variation, the use of pla-

telet function tests may aid the optimization of the timing of surgical

procedures. However, platelet function tests could also be of value

to establish the grade of platelet inhibition in patients in whom the

time since discontinuation is unclear, e.g. in unconscious or confused

patients, and in patients with uncertain compliance to the treatment.

Treatment monitoring, using bedside tests, has been suggested as

an option for guiding interruption of treatment, rather than the use

of an arbitrary, specified period of time.

156,157

Pre-operative ADP-

dependent platelet aggregation capacity predicts CABG-related

Dual antiplatelet therapy in patients treated with cardiac surgery with stable or unstable coronary artery disease

Recommendations Class

Level

It is recommended that the heart team estimates the individual bleeding and ischaemic risks, and guides the timing of

CABG as well as the antithrombotic management.

I C

In patients on aspirin who need to undergo non-emergent cardiac surgery, it is recommended to continue aspirin at a low

daily regimen throughout the perioperative period.

I C

In patients treated with DAPT after coronary stent implantation who subsequently undergo cardiac surgery, it is recom-

mended to resume P2Y

inhibitor therapy post-operatively as soon as is deemed safe so that DAPT continues until the

recommended duration of therapy is completed.

I C

In patients with ACS (NSTE-ACS or STEMI) treated with DAPT, undergoing CABG, and not requiring long-term OAC ther-

apy, resumption of P2Y

inhibitor therapy as soon as is deemed safe after surgery and continuation up to 12 months is

recommended.

I C

In patients on P2Y

inhibitors who need to undergo non-emergent cardiac surgery, postponing surgery for at least 3

days after discontinuation of ticagrelor, at least 5 days after clopidogrel, and at least 7 days after prasugrel should be

considered.

152,153,160

IIa B

In CABG patients with prior MI who are at high risk of severe bleeding (e.g. PRECISE-DAPT >_25), discontinuation of P2Y

inhibitor therapy after 6 months should be considered.

IIa C

Platelet function testing may be considered to guide decisions on timing of cardiac surgery in patients who have recently

received P2Y

inhibitors.

169,172–174

IIb B

In patients perceived to be at high ischaemic risk with prior MI and CABG, who have tolerated DAPT without a bleed-

ing complication, treatment with DAPT for longer than 12 and up to 36 months may be considered.

IIb C

ACS = acute coronary syndrome; CABG = coronary artery bypass graft surgery; DAPT = dual antiplatelet therapy; MI = myocardial infarction; NSTE-ACS = non-ST-elevation

acute coronary syndrome; OAC = oral anticoagulant; PRECISE-DAPT = PREdicting bleeding Complications in patients undergoing Stent implantation and subsEquent Dual Anti

Platelet Therapy; STEMI = ST-elevation myocardial infarction.

Class of recommendation.

Level of evidence.

236 ESC Guidelines

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bleeding complications in clopidogrel-

172–174

and ticagrelor-

treated

169

ACS patients, and a strategy based on pre-operative plate-

let function testing, to determine the timing of CABG in clopidogrel-

treated patients, led to a 50% shorter waiting time than that sug-

gested by a simple discontinuation time-based strategy.

175

It should

be pointed out that the different platelet function tests and their

respective cut-off levels are not interchangeable.

176

Taken together,

these results suggest that platelet function testing in ACS patients

referred for CABG is of potential value to guide the timing of surgery

in patients treated with P2Y

inhibitors. However, randomized stud-

ies with clinically relevant endpoints are lacking.

5.3 Dual antiplatelet therapy for

prevention of graft occlusion

Two meta-analyses have compared graft patency in patients treated

with ASA alone or ASA þ clopidogrel after CABG.

149,177

The studies

included in the meta-analyses comprised mainly patients with stable

CAD. In a meta-analysis by Deo et al,

149

ASA þ clopidogrel was asso-

ciated with a significant reduction in saphenous vein graft occlusions

(RR 0.59, 95% CI 0.43–0.82; P = 0.02). In the meta-analysis by

Nocerino et al,

177

DAPT was consistently associated with a reduced

occlusion rate (RR 0.63, 95% CI 0.46–0.86). DAPT proved useful in

preventing vein graft occlusion (RR 0.58, 95% CI 0.42–0.83), while no

clear effect was shown in arterial grafts (RR 0.85, 95% CI

0.39–1.85).

177

Weak evidence indicates that DAPT may prevent graft

occlusion in patients undergoing off-pump CABG rather than on-

pump CABG.

178

Given the low risk of thrombotic events after

CABG in stable patients, there is insufficient evidence to generally

recommend DAPT post-operatively to reduce vein graft occlusion in

this surgical patient subset.

5.4 Gaps in the evidence

There are several gaps in the evidence that pertain to the use

of DAPT in cardiac surgery. Clear gaps in evidence related to DAPT

in cardiac surgery patients include the question of whether DAPT

should be started after CABG in patients with stable CAD. Also, the

exact timing of post-operative DAPT restart remains unclear, and it

remains uncertain for how long the post-operative DAPT should last.

Further gaps in the evidence relate to: the optimal time point for dis-

continuation of the different P2Y

inhibitors; the optimal use of pla-

telet function testing in patients awaiting cardiac surgery; how to

manage perioperative bleeding complications in cardiac surgery

patients caused by DAPT; and whether and how an incomplete

response or inadequate antiplatelet effect of aspirin after CABG

should be addressed.

6. Dual antiplatelet therapy for

patients with medically managed

acute coronary syndrome

The evidence for the use of DAPT in medically managed ACS

patients comes from the CHARISMA and CURE for

clopidogrel,

40,95

TRILOGY for prasugrel,

and PLATO and

PEGASUS for ticagrelor studies.

20,29

There is no evidence in

favour of prasugrel treatment in patients with ACS who are medi-

cally managed, based on the negative results of the TRILOGY

study and the exclusion of this patient subset in the TRITON

study.

23,24

The CURE study showed a consistent benefit in ACS

patients undergoing an average mean of 9 months DAPT in the

form of aspirin and clopidogrel as compared to 1-month therapy

in NSTE-ACS patients, irrespective of the final management strat-

egy, including or not including coronary revascularization.

The

post-MI subset of patients in the CHARISMA trial derived signifi-

cant benefit with an NNT for benefit in the range of 100, which

came at the expense of higher major bleeding, with an NNT for

harm of 90.

135

While the post-MI population represents only a

subset of those included in the CHARISMA study and the overall

results of the trial did not show benefit of DAPT as compared to

aspirin alone, it seems justifiable to give credit to this subanalysis

based on the consistency of results within multiple recent studies;

these studies showed that the long-term administration of an

intensified antiplatelet regimen beyond 1 year of treatment

reduced long-term ischaemic recurrences, even if at the cost of

higher bleeding.

29,179

Patients medically managed in the PLATO trial derived consistent

benefit from ticagrelor 90 mg b.i.d. as compared to clopidogrel.

Overall mortality was also reduced in patients treated with ticagrelor

90 mg b.i.d.

180

In the PEGASUS trial, 4271 patients had no prior coronary stent

implantation and they derived consistent benefits and risks from tica-

grelor vs. placebo on top of aspirin compared to patients with prior

stenting.

Multiple sources have shown that medically managed ACS patients

are less frequently treated with a DAPT regimen as compared to

patients who received PCI.

181

Current evidence, especially for tica-

grelor, does not support this practice and clinicians should refrain

from tailoring the implementation and/or duration of a DAPT regi-

men depending on prior coronary stent implantation in the current

era of newer-generation DES (Figure 6).

A special population that warrants specific consideration com-

prises patients with established NSTE-ACS in whom no lumen

obstruction at coronary angiography is detected. No dedicated

study exists assessing the benefits and risks of DAPT in this patient

subset. However, a high prevalence of ruptured plaques has been

observed at intravascular imaging modalities in this population,

182

suggesting that the benefits of DAPT in preventing recurrent MI

should not be withheld from these patients if the risk of bleeding

does not outweigh the anticipated benefit.

The evidence in support of the DAPT treatment option in

patients with STEMI conservatively managed or with prior lysis is

limited to 1 month of treatment.

31,32

Yet, in consideration of the

fact that the majority of these patients would undergo invasive

management afterwards, and evidence that DAPT may be benefi-

cial irrespective of whether revascularization takes place, it is rea-

sonable to prolong DAPT further in these patients depending on

the bleeding risk.

ESC Guidelines 237

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7. Dual antiplatelet therapy for

patients with indication for oral

anticoagulation

7.1 Risk stratification and strategies to

improve outcome after percutaneous

coronary intervention

Approximately 6–8% of patients undergoing PCI have an indication for

long-term oral anticoagulants (OACs) due to various conditions such

as AF, mechanical heart valves, or venous thromboembolism.

Compared with oral anticoagulation therapy alone, the addition of

DAPT to OAC therapy results in at least a two- to threefold increase

in bleeding complications.

183–186

Therefore, these patients should be

considered at high risk of bleeding, and the indication for OAC should

be reassessed and treatment continued only if a compelling indication

exists {e.g. paroxysmal, persistent, or permanent AF with a CHA

VASc [Cardiac failure, Hypertension, Age >_75(2points),Diabetes,

Stroke (2 points)–Vascular disease, Age 65–74, Sex category] score

>_1 in men, >_2 in women; mechanical heart valve; recent (i.e. 6 months)

or a history of recurrent deep venous thrombosis or pulmonary

embolism}. Conversely, every effort should be undertaken to imple-

ment strategies to minimize PCI-related complications in these patients

(Tab le 4). In particular, the duration of triple therapy should be limited

or omitted after hospital discharge (i.e. confined to the periprocedural

phase with aspirin being stopped thereafter), taking into account the

ischaemic (e.g. complexity of treated CAD, amount of disease left

untreated, technical considerations regarding stent implantation techni-

ques, and results) as well as the bleeding risks. While ischaemic risk

scores also predict bleeding outcomes in AF,

187

suggesting consider-

able overlap among risk factors associated with ischaemic and bleeding

outcomes, multiple bleeding risk scores,

188

including the HAS-BLED

189

[Hypertension, Abnormal renal and liver function (1 point each),

Stroke, Bleeding history or predisposition, Labile INR, Elderly (>

65 years), Drugs and alcohol (1 point each)] score, have been shown

to outperform CHADS

[Cardiac failure, Hypertension, Age, Diabetes,

Stroke (Doubled)] or CHA

-VASc in predicting bleeding risk.

Importantly, HAS-BLED draws attention to the reversible bleeding

risk factors to be addressed by the responsible clinician during the fol-

low-up. Risk is not static and, particularly for bleeding, many risk factors

can be modified. Hence, a high risk of bleeding (e.g. HAS-BLED score

>_3) is not a reason to withhold OAC; instead, such patients should be

‘flagged-up’ for more careful review and follow-up.

More recently, the novel biomarker-based ABC [Age, Biomarkers

(GDF-15, cTnT-hs, and haemoglobin), and Clinical history (previous

bleeding)]

190

bleeding risk score has been generated and validated in

a broad AF population treated with both vitamin K antagonist (VKA)

and non-vitamin K oral anticoagulants (NOACs), and has shown

superior prediction capability as compared to HAS-BLED. However,

similar to all other bleeding risk scores, none of these risk prediction

models developed for OAC patients has been prospectively tested in

the setting of prospective RCTs. Therefore, their value in improving

patient outcomes remains unclear.

A comprehensive list of all risk factors that have been associated

with greater bleeding risk has been previously published.

162

In the absence of safety and efficacy data from RCTs [only 6% of

patients were treated at baseline with ticagrelor or prasugrel in the

Rivaroxaban and a dose-adjusted oral VKA treatment strategy in

Dual antiplatelet therapy duration in patients with acute coronary syndrome undergoing medical therapy

management.

Recommendations Class

Level

In patients with ACS who are managed with medical therapy alone and treated with DAPT, it is recommended to con-

tinue P2Y

inhibitor therapy (either ticagrelor or clopidogrel) for 12 months.

20,40

I A

Ticagrelor is recommended over clopidogrel, unless the bleeding risk outweighs the potential ischaemic beneﬁt.

I B

In patients with medically managed ACS who are at high risk of bleeding (e.g. PRECISE-DAPT >_25), DAPT for at least

1 month should be considered.

IIa C

In patients with prior MI at high ischaemic risk

who are managed with medical therapy alone and have tolerated DAPT

without a bleeding complication, treatment with DAPT in the form of ticagrelor 60 mg b.i.d. on top of aspirin for longer

than 12 months and up to 36 months may be considered.

139

IIb B

In patients with prior MI not treated with coronary stent implantation, who have tolerated DAPT without a bleeding complica-

tion and who are not eligible for treatment with ticagrelor, continuation of clopidogrel on top of aspirin for longer than

12 months may be considered.

IIb C

Prasugrel is not recommended in medically managed ACS patients.

III B

ACS = acute coronary syndrome; b.i.d.=bis in die; CrCl = creatinine clearance; DAPT = dual antiplatelet therapy; MI = myocardial infarction; PRECISE-DAPT = PREdicting

bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy.

Class of recommendation.

Level of evidence.

Deﬁned as >_ 50 years of age, and one or more of the following additional high-risk features: age of 65 years or older, diabetes mellitus requiring medication, a second prior

spontaneous myocardial infarction, multivessel coronary artery disease, or chronic renal dysfunction, deﬁned as an estimated creatinine clearance < 60 mL/min.

238 ESC Guidelines

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subjects with atrial fibrillation who undergo percutaneous coronary

intervention (PIONEER AF-PCI) study

191

] and worrisome bleeding

signals in registries, the use of prasugrel or ticagrelor as part of triple

therapy should be avoided.

192

Gastric protection with a PPI is recom-

mended. The dose intensity of OAC should be carefully monitored

with a target international normalized ratio (INR) in the lower part of

the recommended target range; in patients treated with NOACs, the

lowest effective tested dose for stroke prevention should be applied

and criteria for drug accumulation for each approved NOAC should

be carefully assessed. Lower NOAC regimens as compared to those

tested in approval studies are expected to decrease bleeding risk, but

the trade-off between bleeding and ischaemic (i.e. stroke prevention)

outcomes remains largely undefined. The PIONEER AF-PCI study

191

(described in detail below) tested two lower rivaroxaban doses

(15 mg o.d. and 2.5 mg b.i.d.) as compared to the approved drug regi-

men in AF patients (20 mg q.d.). The Evaluation of Dual Therapy With

Dabigatran vs. Triple Therapy With Warfarin in Patients With AF

That Undergo a PCI With Stenting (REDUAL-PCI; NCT02164864)

will compare two dabigatran doses (150 mg b.i.d. and 110 mg b.i.d.)vs.

VKA and will provide additional insights with respect to the balance

between efficacy and safety for each one. Whether there are differ-

ences according to the type of OAC (NOACs vs. VKA) or stent plat-

form as well the duration of triple therapy is further discussed. These

considerations do not pertain to medically managed patients or to

patients eligible for CABG surgery in whom DAPT should be avoided

on top of OAC.

7.2 Duration of triple therapy

Cessation of aspirin after PCI while maintaining clopidogrel has been

evaluated in the What is the Optimal antiplatElet and anticoagulant

Table 4 Strategies to avoid bleeding complications in

patients treated with oral anticoagulant

ABC = Age, Biomarkers, Clinical history; CHA

-VASc = Congestive heart

failure, Hypertension, Age >_75 years (doubled), Diabetes mellitus, prior Stroke

or transient ischaemic attack or thromboembolism (doubled), Vascular disease,

Age 65–74 years, Sex category; HAS-BLED = Hypertension, Abnormal renal/liver

function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/

alcohol concomitantly; NOAC = non-vitamin-K oral anticoagulant; INR = inter-

national normalized ratio; PCI = percutaneous coronary intervention; PPIs = pro-

ton pump inhibitors; VKA = vitamin K antagonist.

Apixaban 5 mg b.i.d or apixaban 2.5 mg b.i.d. if at least two of the following: age

>_80 years, body weight <_60 kg or serum creatinine level >_1.5 mg/dL (133 lmol/

L); dabigatran 110 mg b.i.d.; edoxaban 60 mg q.d. or edoxaban 30 mg q.d. if any of

the following: creatinine clearance (CrCl) of 30–50 mL/min, body weight <_60 kg,

concomitant use of verapamil or quinidine or dronedarone; rivaroxaban 20 mg

q.d. or rivaroxaban 15 mg q.d. if CrCl 30–49 mL/min.

Figure 6 Algorithm for dual antiplatelet therapy (DAPT) in

patients with acute coronary syndrome undergoing medical manage-

ment. High bleeding risk is considered as an increased risk of sponta-

neous bleeding during DAPT (e.g. PRECISE-DAPT score >_25).

Colour-coding refers to the ESC Classes of Recommendations

(green = Class I; yellow = IIa; orange = Class IIb). Treatments pre-

sented within the same line are sorted in alphabetic order, no prefer-

ential recommendation unless clearly stated otherwise.

1: if patient is not eligible for a treatment with ticagrelor

ESC Guidelines 239

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therapy in patients with OAC and coronary StenTing (WOEST) trial,

which randomized 573 patients (of whom 69% of patients had AF) to

dual therapy with OAC and clopidogrel (75 mg/day) or to triple ther-

apy with OAC, clopidogrel, and aspirin 80 mg/day.

193

Treatment was

continued for 1 month after BMS placement and for 1 year after DES

placement (65% of patients). PCI was performed on VKA therapy in

half of the patients. The primary endpoint of any TIMI bleeds assessed

at 1-year follow-up was significantly reduced in the dual-therapy arm

(19.5% vs. 44.9%; HR 0.36, 95% CI 0.26–0.50; P < 0.001), while no sig-

nificant difference in major bleeding was observed. The rates of MI,

stroke, target vessel revascularization, or stent thrombosis did not

differ significantly, but all-cause mortality was lower in the dual-

therapy group (2.5% vs. 6.4%; P = 0.027) at 1 year.

More recently, the PIONEER AF-PCI study randomized 2124

patients with non-valvular AF who had undergone PCI with stenting

to receive, in a 1:1:1 ratio: low-dose rivaroxaban (15 mg o.d.)plusa

P2Y

inhibitor (and no ASA) for 12 months; very-low-dose rivaroxa-

ban (2.5 mg b.i.d.) plus DAPT for 1, 6, or 12 months; or standard ther-

apy with a dose-adjusted VKA plus DAPT for 1, 6, or 12 months.

191

The primary safety endpoint, consisting of TIMI clinically significant

bleeding, was lower in the two groups receiving rivaroxaban than in

the group receiving standard therapy [16.8% in patients treated with

rivaroxaban 15 mg, 18% in patients treated with rivaroxaban 2.5 mg,

and 26.7% in patients treated with triple therapy (HR 0.59, 95% CI

0.47–0.76; P < 0.001, and HR 0.63, 95% CI 0.50–0.80; P < 0.001,

respectively)]. It is worth mentioning that as many as 49% of patients

Figure 7 Algorithm for dual antiplatelet therapy (DAPT) in patients with an indication for oral anticoagulation undergoing percutaneous coronary

intervention (PCI). Colour-coding refers to the number of concomitant antithrombotic medication(s). Triple therapy denotes treatment with DAPT

plus oral anticoagulant (OAC). Dual therapy denotes treatment with a single antiplatelet agent (aspirin or clopidogrel) plus OAC.

ABC = age, biomarkers, clinical history; ACS = acute coronary syndrome; mo. = month(s); PCI = percutaneous coronary intervention.

1: Periprocedural administration of aspirin and clopidogrel during PCI is recommended irrespective of the treatment strategy.

2: High ischaemic risk is considered as an acute clinical presentation or anatomical/procedural features which might increase the risk for

myocardial infarction.

3: Bleeding risk can be estimated by HAS-BLED or ABC score.

240 ESC Guidelines

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in both DAPT groups continued triple therapy for 12 months and no

difference in major bleeding or transfusion was observed across the

groups. Moreover, an INR range of 2–3 was recommended, instead

of 2–2.5, which may have inflated bleeding risk in the control group.

The rates of all-cause death, death from cardiovascular causes, MI, or

stroke were similar in the three groups.

194

However, this study, simi-

lar to WOEST, was largely underpowered for the assessment of

meaningful differences in the incidence of relevant ischaemic events

such as stent thrombosis or stroke rates. Therefore, uncertainty

remains regarding the comparative performance of three tested

antithrombotic regimens in patients at high stroke and/or stent

thrombosis risk. Procedural characteristics of coronary intervention

have not been reported so far and patients with prior stroke were

excluded from participation. As a result, the balance of ischaemic and

bleeding risks of relatively short (i.e. 6 months or less) triple therapy

duration (possibly with NOAC instead of VKA) as compared to dou-

ble therapy consisting of clopidogrel and OAC remains unknown and

requires a patient-by-patient decision.

Dual therapy with clopidogrel and OAC after PCI remains an

appealing alternative to triple therapy given that patients exposed to

OAC are at high bleeding risk, but more data, especially on efficacy

and particularly in patients at high risk for stroke and/or recurrent

ACS, are needed. Cessation of clopidogrel while maintaining aspirin

has also been tested in the Triple Therapy in Patients on Oral

Anticoagulation After Drug Eluting Stent Implantation (ISAR-TRIPLE)

trial, where 614 patients (one-third with ACS) undergoing stenting

and requiring OAC were randomly assigned to receive either 6-

week or 6-month clopidogrel therapy in addition to aspirin and

VKA.

195

The primary endpoint of death, MI, stent thrombosis, ischae-

mic stroke, or TIMI major bleeding at 9 months did not differ

between the 6-week and 6-month triple therapy (9.8% vs. 8.8%; HR

1.14, 95% CI 0.68–1.91; P = 0.63); the same was true for the com-

bined incidence of death, MI, stent thrombosis, and ischaemic stroke

(4.0% vs. 4.3%; HR 0.93, 95% CI 0.43–2.05; P = 0.87). Furthermore,

no difference in TIMI major bleeding (5.3% vs. 4.0%; HR 1.35, 95% CI

0.64–2.84; P = 0.44) was observed.

In all three studies, roughly one-third of patients presented with ACS.

There was no interaction between the duration of triple therapy and clini-

cal presentation (ACS vs. no ACS), which may reflect a real lack of

increased coronary ischaemic risk in these patients or a lack of power to

detect clinically meaningful differences in coronary ischaemic outcomes if

these patients undergo shorter duration of DAPT regimen (i.e. 1 month

195

or immediate discontinuation of aspirin after PCI

191,193

).Therateofbleed-

ing events peaked within the first 30 days of initiation of triple therapy

and was twice as high when compared with the rate of acute coronary

events including recurrent MI and stent thrombosis. These observa-

tions are consistent with the nationwide Danish registry of AF all-

comers with MI, where the 90-day bleeding risk was increased on triple

therapycomparedwithOACplusasingle antiplatelet agent (HR 1.47,

95% CI 1.04–2.08), with a consistent trend at 360 days (HR 1.36, 95%

CI 0.95–1.95), without differences in ischaemic events (HR 1.15, 95%

CI 0.95–1.40).

196

The same registry suggests that warfarin plus clopi-

dogrel resulted in a non-significant reduction in major bleeds (HR 0.78,

95% CI 0.55–1.12) compared with triple therapy, with a non-significant

reduction in MI or coronary death (HR 0.69, 95% CI 0.55–1.12).

197

For

these reasons, duration of triple therapy should be minimized depend-

ing on bleeding and ischaemic risks (Figure 7; Tables 5 and 6).

Dual antiplatelet therapy duration in patients with indi-

cation for oral anticoagulation

Recommendations Class

Level

It is recommended to administer periproce-

durally aspirin and clopidogrel in patients

undergoing coronary stent implantation.

I C

In patients treated with coronary stent implan-

tation, triple therapy with aspirin, clopidogrel,

and OAC should be considered for 1 month,

irrespective of the type of stent used.

195

IIa B

Triple therapy with aspirin, clopidogrel, and

OAC for longer than 1 month and up to

6 months should be considered in patients

with high ischaemic risk due to ACS or

other anatomical/procedural characteristics

that outweigh the bleeding risk.

195

IIa B

Dual therapy with clopidogrel 75 mg/day

and OAC should be considered as an alter-

native to 1-month triple antithrombotic

therapy in patients in whom the bleeding

risk outweighs the ischaemic risk.

191,193

IIa A

Discontinuation of antiplatelet treatment in

patients treated with OAC should be con-

sidered at 12 months.

198

IIa B

In patients with an indication for VKA in combi-

nation with aspirin and/or clopidogrel, the dose

intensity of VKA should be carefully regulated

with a target INR in the lower part of the rec-

ommended target range and a time in the ther-

apeutic range >65–70%.

193,195

IIa B

When a NOAC is used in combination with

aspirin and/or clopidogrel, the lowest approved

dose effective for stroke prevention tested in

AF trials should be considered.

IIa C

When rivaroxaban is used in combination with

aspirin and/or clopidogrel, rivaroxaban 15 mg q.d.

may be used instead of rivaroxaban 20 mg q.d.

191

IIb B

The use of ticagrelor or prasugrel is not rec-

ommended as part of triple antithrombotic

therapy with aspirin and OAC.

III C

ACS = acute coronary syndrome; AF = atrial ﬁbrillation; b.i.d.=bis in die;CrCl=creati-

nine clearance; INR = international normalized ratio; NOAC = non-vitamin K oral anti-

coagulant; OAC = oral anticoagulant; q.d.=quaque die; VKA = vitamin K antagonist.

Class of recommendation.

Level of evidence.

Apixaban 5 mg b.i.d or apixaban 2.5 mg b.i.d. if at least two of the following: age

>_80 years, body weight <_60 kg or serum creatinine level >_1.5 mg/dL (133 lmol/

L); dabigatran 110 mg b.i.d.; edoxaban 60 mg q.d. or edoxaban 30 mg q.d. if any of

the following: CrCl of 30–50 mL/min, body weight <_60 kg, concomitant use of

verapamil, quinidine, or dronedarone; rivaroxaban 20 mg q.d. or rivaroxaban

15 mg q.d. if CrCl 30–49 mL/min.

ESC Guidelines 241

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7.3 Cessation of all antiplatelet agents

Data on the timing of cessation of any antiplatelet agents in stented

patients requiring chronic OAC are scarce. In stabilized event-free

patients, discontinuation of any antiplatelet agent at 1 year after stent-

ing is encouraged in this patient population based on studies demon-

strating that OACs alone are superior to aspirin post-ACS, and OAC

þ aspirin may not be more protective but associated with excess

bleeding.

198

Dual therapy with OAC and one antiplatelet agent

(aspirin or clopidogrel) may be considered beyond 1 year in patients

at very high risk of coronary events as defined in Table 5

and in

patients with mechanical prosthesis and atherosclerotic disease.

7.4 Type of anticoagulants

PIONEER AF-PCI is the only randomized study comparing VKAs and

NOACsinpatientswithAFundergoingPCIforACSorforstableCAD

(i.e. patients who have an indication to receive DAPT).

191

However, in

this study, two non-approved rivaroxaban regimens for AF patients

were tested and a low (i.e. 15 mg q.d.) or very low (i.e. 2.5 mg b.i. d.)rivar-

oxaban dose in combination with a single P2Y

inhibitor or DAPT was

compared to VKA plus DAPT, respectively. The study was

underpowered for ischaemic endpoints. Therefore, no conclusion can

be made on the advantages and limitations of each OAC as compared

to others. However, there was an excess of stroke events in the 2.5 mg

b.i.d. rivaroxaban arm in combination with 6-month DAPT as compared

to VKA and 6-month DAPT (6 vs. 0 events; P = 0.02).

In the four phase III NOAC AF trials, no interactions were demon-

strated between treatment effect and outcome according to prior

coronary status (ACS vs. no ACS), and it is likely that the benefit of

NOAC over VKA is preserved in CAD patients with AF.

199–202

least, this was the case among patients exposed to antiplatelet ther-

apy. There is no strong evidence for choosing one NOAC over

another. Dabigatran is the only NOAC that has been tested in a

phase III trial at reduced daily regimen (i.e. 110 mg b.i.d.) and for which

non-inferiority vs. warfarin was shown.

199

Although lower doses of

other NOACs (i.e. apixaban 2.5 mg b.i.d. or edoxaban 30 mg o.d.)

might be considered to reduce bleeding risk, these dosages have

been evaluated only in a subset of patients in the phase III trials based

on prespecified dosing algorithms. Their benefit in stroke prevention

in patients with a normal renal function is uncertain. Three ongoing

large-scale outcome studies are evaluating combinations of NOACs

or VKAs with antiplatelet therapy in AF patients undergoing stent-

PCI (NCT02164864, NCT02415400, and NCT02866175). Various

dose regimens of NOAC, different types of P2Y

inhibitors, and dif-

ferent exposure times are being evaluated.

7.5 Type of stent

The choice of newer-generation DES vs. BMS in patients requiring

long-term anticoagulation is no longer controversial. First, data from

the DAPT trial indicate a similar impact of prolonged DAPT adminis-

tration irrespective of stent type (BMS vs. DES),

128

and the risk of

adverse events among patients with DAPT cessation and patients

undergoing non-cardiac surgery indicate no differences between

BMS and DES.

17,129,203

Second, two randomized trials have demon-

strated the superiority of newer-generation DES over BMS in high

bleeding risk patients who cannot tolerate long-term exposure to

DAPT,

130,204

such as those needing chronic OAC (section 2.2).

Altogether, both trials suggest that second-generation DES should

be the default choice in patients with high bleeding risk.

8. Elective non-cardiac surgery in

patients on dual antiplatelet

therapy

It is estimated that 5–25% of patients with coronary stents may

require non-cardiac surgery within 5 years after stent implantation.

205

Management of patients on DAPT who are referred for surgical pro-

cedures involves consideration of: (1) the risk of stent thrombosis

(particularly if DAPT needs to be interrupted); (2) the consequences

of delaying the surgical procedure; and (3) the increased intra- and

periprocedural bleeding risk and possible consequences of such

bleeding if DAPT is continued.

206–208

Given the complexity of these

considerations, a multidisciplinary approach—involving interven-

tional cardiologists, cardiologists, anaesthetists, haematologists, and

surgeons—is required to determine the patient’s risk for bleeding

and thrombosis and to choose the best management strategy.

Table 5 High-risk features of stent-driven recurrent

ischaemic events

Table 6 Unfavourable patient proﬁle for a combina-

tion of oral anticoagulant and antiplatelet therapy

242 ESC Guidelines

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Surgical interventions can be divided into low-risk, intermediate-risk,

and high-risk groups, with estimated 30-day cardiac event rates

for cardiac death or MI of < 1%, 1–5%, and >_5%, respectively.

205,209

A practical classification of the bleeding risk associated with each type

of non-cardiac surgery has been recently proposed by the Stent

After Surgery group.

210

In surgical procedures with low bleeding risk, every effort should be

taken not to discontinue DAPT perioperatively. In surgical procedures

with moderate bleeding risk, patients should be maintained on aspirin

while P2Y

inhibitor therapy should be discontinued whenever possi-

ble. More challenging decision makingistobefacedamongpatientson

DAPT who undergo high bleeding risk non-cardiac surgeries, including

vascular reconstructions, complex visceral procedures, neurosurgery,

and transbronchial operations.

211–213

In these cases, particular atten-

tion should be paid to timely discontinuation of P2Y

inhibitor therapy

to minimize the off-therapy period before surgical intervention.

Discontinuation before non-cardiac surgery: To reduce the risk of

bleeding and transfusion, it is recommended to postpone elective

non-cardiac surgery until completion of the full course of DAPT. In

most clinical situations, aspirin provides benefit that outweighs the

bleeding risk and should be continued.

214,215

Possible exceptions to

this recommendation include intracranial procedures, transurethral

prostatectomy, intraocular procedures, and operations with

extremely high bleeding risk.

157

A higher risk of ischaemic events in the case of non-cardiac surgery

has been reported after first-generation DES

203

and a higher risk for

MACE has also been shown during the first weeks after non-cardiac

surgery in patients with implanted stents.

203,216,217

Furthermore, sur-

gery per se, irrespective of the timing of DAPT discontinuation, is

associated with pro-inflammatory and pro-thrombotic effects,

thereby increasing the risk of coronary thrombosis at the level of the

stented vascular segment as well as throughout the coronary vascula-

ture.

218,219

Therefore, in patients undergoing non-cardiac surgery

after recent ACS or stent implantation, the benefits of early surgery

for a specific pathology (e.g. malignant tumours or vascular aneurysm

repair) should be balanced against the risk of cardiovascular events

and the strategy should be discussed by a multidisciplinary team.

Prior recommendations with regard to duration of DAPT

220,221

and the timing of non-cardiac surgery

207,222

in patients treated with

DES were based on observations of those treated with first-

generation DES. Compared with first-generation DES, currently used

newer-generation DES are associated with a lower risk of stent

thrombosis and appear to require a shorter minimum duration of

DAPT.

100,103,104,223–225

Furthermore, in the PARIS registry, interrup-

tion of DAPT grounded on physician judgment in patients undergoing

surgery at any time point after PCI was not associated with an

increased risk of MACE.

In the absence of a surgical control group, it remains challenging to

identify a clear time frame after ACS or coronary stenting where

there is no additional risk or the risk is acceptably low for patients to

undergo surgery. Therefore, almost all registries have attempted to

identify such landmarks by looking at the time course of the surgical

ischaemic risk over time in order to identify when it levels off and

remains stable thereafter following an ACS or stent implantation pro-

cedure.

By doing so, many registries have reported that surgery-

associated risk in DES-PCI-treated patients reaches a stable level

after 3–6 months.

17,214,215

However, without a surgical control

group, these findings are potentially influenced by the type and

urgency of the surgical procedures. To overcome this limitation, two

large matched cohorts of patients undergoing surgery were recently

reported. Using Danish population-based registries and individual-

based record linkage of Danish registries, 4303 DES-PCI-treated

patients who underwent a surgical procedure within 12 months were

identified and were compared with a control group of patients with-

out established stable CAD undergoing similar surgical procedures (n

= 20 232).

226

This evaluation of the comparative risk associated with

surgery in DES-PCI-treated patients vs. patients without known sta-

ble CAD revealed an increased overall risk for MI and cardiac death

in the patients with previous DES-PCI, owing to higher MI rates but

similar mortality risk.

226

However, this difference was highly time-

dependent and limited to the first month after DES-PCI.

226

These

data suggest that surgery, if possible, should be delayed for at least

1 month after DES-PCI. Data for patients with coronary stents

implanted in a Veterans’ Administration (VA) hospital from 2000 to

2010 were also recently matched with VA Surgical Quality

Improvement Program data to identify non-cardiac surgery within

24 months of stent placement.

227

Each patient with a stent(s) was

matched with two surgical patients without stents on surgical charac-

teristics and cardiac risk factors. The two groups had similar risk of

adverse cardiac events during 2 years of follow-up. However, patients

with stents had a higher risk of adverse cardiac events within the

30-day post-operative period.

227

The incremental risk did not vary by

stent type.

227

In both studies, roughly 50% of patients underwent

stenting because of ACS and no incremental risk was observed in this

higher risk population as compared to stable CAD patients.

Therefore, a minimum of 1 month of DAPT should be considered,

independently of the type of implanted stent (i.e. BMS or newer-gen-

eration DES), in cases when surgery cannot be delayed for a longer

period; however, such surgical procedures should be performed in

hospitals where catheterization laboratories are available 24/7, so as

to treat patients immediately in case of perioperative thrombotic

events (Figure 8). In patients at high ischaemic risk due to ACS pre-

sentation or complex coronary revascularization procedure, delaying

surgery up to 6 months after index ACS or PCI may be reasonable as

an additional safeguard to minimize the risk of perisurgical MI, and

based on unmatched retrospective registry data if the risks of further

delaying surgery are acceptable.

In patients needing surgery within a few days, it was previously rec-

ommended to withhold clopidogrel and ticagrelor for 5 days and pra-

sugrel for 7 days prior to surgery unless there is a high risk of

thrombosis.

228

However, emerging evidence, which is extensively

discussed in Chapter 5, challenges such a long discontinuation period

for ticagrelor before a safe surgical procedure can be undertaken

(Figure 9).

152,153

Although these data refer to patients undergoing cardiac surgery,

it is rational to extend these findings to the non-cardiac surgery popu-

lation, given the same offset kinetics and principally lower risk of

bleeding in non-cardiac surgeries relative to cardiac surgery proce-

dures (Figure 9). In cases where the consequences of even minor

bleeding would be unacceptable (e.g. spinal surgery or other neuro-

surgical procedures) or the bleeding risk largely outweighs the ischae-

mic risk (e.g. a medium- to high-risk surgical bleeding procedure is

undertaken 6 months or more after single stent implantation for sta-

ble CAD indication), P2Y

inhibitors may be discontinued for a

ESC Guidelines 243

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longer duration of time to ensure no residual platelet inhibition at the

time of planned surgery. For patients with a very high risk of stent

thrombosis, bridging therapy with intravenous, reversible glycopro-

tein inhibitors, such as eptifibatide or tirofiban,

229

may be considered.

Cangrelor, a reversible intravenous P2Y

inhibitor, has been shown

to provide effective platelet inhibition

230

and is an appealing alterna-

tive to glycoprotein IIb/IIIa inhibitors,

231

given the well-known role of

P2Y

inhibition in preventing stent thrombosis and the quicker offset

of action as compared to tirofiban or eptifibatide. Concomitant

parenteral anticoagulation therapy in conjunction with cangrelor or

reversible glycoprotein inhibitors is not recommended to minimize

bleeding risk while awaiting surgical procedures.

Restart after surgery: If P2Y

inhibitor therapy has been stopped

before a surgical procedure, therapy should be restarted as soon

as possible (within 48 h), given the substantial thrombotic hazard

associated with lack of platelet inhibition early after surgery in

patients with recent stent implantation and/or an ACS episode

(Figure 9).

232,233

The time for restarting P2Y

inhibitors after surgery should ulti-

mately be determined via a multidisciplinary discussion before sur-

gery and traced in the patient file.

Dual antiplatelet therapy in patients undergoing elec-

tive non-cardiac surgery

Recommendations Class

Level

It is recommended to continue aspirin peri-

operatively if the bleeding risk allows, and to

resume the recommended

antiplatelet therapy as soon as possible

post-operatively.

232–236

I B

After coronary stent implantation, elective

surgery requiring discontinuation of the

P2Y

inhibitor should be considered after

1 month, irrespective of the stent type, if

aspirin can be maintained throughout the

perioperative period.

227

IIa B

Discontinuation of P2Y

inhibitors should

be considered at least 3 days before surgery

for ticagrelor, at least 5 days for

clopidogrel, and at least 7 days for

prasugrel.

152,153,160

IIa B

A multidisciplinary expert team should be

considered for pre-operative evaluation of

patients with an indication for DAPT before

elective surgery.

IIa C

In patients with recent MI or other high

ischaemic risk features

requiring DAPT,

elective surgery may be postponed for up

to 6 months.

17,214,215,234

IIb C

If both oral antiplatelet agents have to be

discontinued perioperatively, a bridging

strategy with intravenous antiplatelet agents

may be considered, especially if surgery has

to be performed within 1 month after stent

implantation.

229,237–239

IIb C

It is not recommended to discontinue

DAPT within the ﬁrst month of treatment

in patients undergoing elective non-cardiac

surgery.

203

III B

DAPT = dual antiplatelet therapy; MI = myocardial infarction.

Class of recommendation.

Level of evidence.

High ischaemic risk features are provided in Table 5.

Figure 8 Timing for elective non-cardiac surgery in patients

treated with dual antiplatelet therapy (DAPT) after percutaneous

coronary intervention (PCI). Colour-coding refers to the ESC

Classes of Recommendations (green = Class I; yellow = IIa; orange

= Class IIb).

ACS = acute coronary syndromes.

Availability of H24 cath-lab service in place is suggested in

case of major surgery within 6 months after PCI.

High ischaemic risk features are presented in Table 5.

244 ESC Guidelines

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9. Gender consideration and

special populations

9.1 Gender specificities

There is no convincing evidence for a gender-related difference in the

efficacy and safety of currently available DAPT type or duration across

studies. No single trial or pooled analysis of investigations assessing a

shorter than 1 year vs. at least 1 year DAPT duration has shown heter-

ogeneous findings across genders.

26,112,240,241

In the DAPT trial, there

was a borderline quantitative interaction suggesting a lower relative

treatment benefit for stent thrombosis reduction with prolonged

DAPT in female as compared to male patients (P

int

=0.04).

However, no such signal was apparent for MACCE (P

int

= 0.46) or

bleeding (P

int

= 0.40) endpoints. Within the PEGASUS trial, there was

no signal suggesting heterogeneity across the primary study endpoint

with respect to gender (P

int

=0.84).

On the other hand, there was a

positive quantitative interaction (P

int

= 0.03) suggesting that female

patients may derive a relatively greater treatment benefit with respect

to stroke prevention from prolonged treatment with aspirin and tica-

grelor as compared to aspirin alone. However, no such signal was evi-

dent for cardiovascular death, MI, or safety endpoints.

9.2 Diabetes mellitus

Patients with diabetes mellitus presenting with both stable and unsta-

ble CAD carry a worse prognosis in terms of short- and long-term

risks of fatal and non-fatal ischaemic events, with enhanced platelet

hyperactivity playing a putative causal role. In the CURE trial, patients

with diabetes derived a similar treatment benefit from the addition of

clopidogrel on top of aspirin as compared to patients without.

signal for greater treatment benefit was apparent in TRITON-TIMI

38 in patients with diabetes as compared to those without with

respect to the study primary endpoint, and a consistent lack of heter-

ogeneity signal with respect to diabetes mellitus was observed in the

PLATO trial.

20,23

Hence, there is no convincing evidence that the

presence of diabetes should affect decision making with respect to

the choice of P2Y

inhibitors.

As it related to DAPT duration, the DAPT study found a slightly

lower relative risk reduction for MI endpoint in patients with diabetes

as compared to those without diabetes (P

int

=0.02).

242

However,

there was no signal for heterogeneity with respect to the concomitant

presence of diabetes mellitus across all other ischaemic or safety end-

points. Finally, no difference with respect to the presence or absence

of diabetes was observed for the primary efficacy endpoint in the

PEGASUS study (P

int

= 0.99).

145

Altogether, current evidence suggests

that diabetes mellitus should not be the only appraised patient-specific

feature when deciding upon the type or duration of DAPT.

9.3 Lower-extremities artery disease

Patients with LEAD are at heightened risk of ischaemic complications

and mortality. The combination of symptomatic LEAD and CAD is

associated with further heightened ischaemic risk beyond that associ-

ated with symptomatic disease in either vascular bed alone.

243

In 3096

patients with LEAD included in the CHARISMA trial, DAPT was asso-

ciated with a lower rate of MI and hospitalization for ischaemic events

but not the overall composite primary endpoint. There was no differ-

ence between the groups in moderate, severe, or fatal bleeding, but

there was an increase in minor bleeding in the DAPT group.

244

The

PEGASUS investigators recently examined a subgroup of 1143 patients

with LEAD and found that patients with prior MI with LEAD had a 60%

increased risk of MACE relative to patients without LEAD, even after

adjusting for differences in baseline characteristics.

140

This increased

ischaemic risk translated into a robust absolute risk reduction of 5.2%

at 3 years with ticagrelor 60 mg b.i.d . compared with placebo. In the set-

ting of this robust ischaemic risk reduction, there were significant

reductions in cardiovascular and all-cause mortality. Treatment with

ticagrelor vs. placebo reduced the risk of adverse limb events in addi-

tion to the benefits observed for MACE and mortality. Reductions in

acute limb ischaemia have also been shown with other antiplatelet

Figure 9 Minimal discontinuation and re-implementation time frames of dual antiplatelet therapy (DAPT) for patients undergoing elective surgery

OAC = oral anticoagulant.

ESC Guidelines 245

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Figure 10 Practical recommendations for the management of bleeding in patients treated with dual antiplatelet therapy with or without concomi-

tant oral anticoagulation. Practical recommendations for the management of bleeding in patients treated with dual antiplatelet therapy with or with-

out concomitant oral anticoagulation. Blue boxes refer to management of antiplatelet therapy. Dark-red boxes refer to the management of oral

anticoagulation. Light-green boxes refer to general recommendation for patients’ safety.

ACS = acute coronary syndrome; CHA

-VASc= cardiac failure, hypertension, age >_75 (2 points), diabetes, stroke (2 points)– vascu-

lar disease, age 65– 74, sex category; DAPT = dual antiplatelet therapy; GI = gastrointestinal; HB = haemoglobin; INR = international

normalized ratio; i.v. = intravenous; OAC = oral anticoagulant; NOAC = non-vitamin-K antagonist; PPI = proton pump inhibitor; RBC

= red blood cell; SAPT = single antiplatelet therapy.

246 ESC Guidelines

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agents, such as vorapaxar, demonstrating that this morbidity is modifi-

able with potent and prolonged antithrombotic strategies.

245

In the all-

comer PRODIGY trial, 246 (12.5%) patients were included with symp-

tomatic LEAD. LEAD status was associated with a higher risk of death

and ischaemic events (HR 2.80, 95% CI 2.05–3.83; P < 0.001).

246

Prolonged vs. short DAPT conveyed a lower risk of the primary effi-

cacy endpoint in LEAD patients (16.1% vs. 27.3%; HR 0.54, 95% CI

0.31–0.95; P = 0.03) but not in patients without LEAD (9.3% vs. 7.4%;

HR 1.28, 95% CI 0.92–1.77; P = 0.14), with positive interaction (P =

0.01). The risk of definite or probable stent thrombosis as well as

Figure 10 Continued

ESC Guidelines 247

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overall mortality was significantly lowerinLEADpatientstreatedwith

prolonged DAPT as compared with those receiving short DAPT.

9.4 Complex percutaneous coronary

intervention

While high PCI complexity intuitively represents a driver for favouring

a prolonged over a shortened DAPT duration, the evidence regarding

optimal DAPT duration based on complexity of intervention is limited.

In a patient-level meta-analysis from six RCTs investigating DAPT

durations after coronary stenting, including 9577 patients, complex

PCI was defined as the composite of at least three stents implanted, at

least three lesions treated, bifurcation with two stents implanted, total

stent length >60 mm, and chronic total occlusion as target lesion.

247

Patients who underwent complex PCI had a two-fold increase of

MACE (5.0% vs. 2.5%; P = 0.001). Long- and short-DAPT were

defined as a DAPT duration >_12 months and <_6 months, respectively.

Compared with short-DAPT, long-DAPT was associated with a signif-

icant reduction in MACE in the complex PCI group (4.0% vs. 6.0%;

adjusted HR 0.56, 95% CI 0.35–0.89) vs. the non-complex PCI group

(2.5% vs. 2.6%; adjusted HR 1.01, 95% CI 0.75–1.35; P

int

=0.01).The

magnitude of the reduction in MACE with long-DAPT increased pro-

gressively as the degree of procedural complexity was greater. Long-

DAPT was overall associated with increased risk of major bleeding,

which was uniform in magnitude between groups (P

int

=0.15).

9.5 Dual antiplatelet therapy decision

making in patients with stent thrombosis

Patients presenting with stent thrombosis represent a challenging

patientpopulationinwhomnorandomized clinical evidence is available

to guide decision making. Observational studies have shown that the

risk of stent thrombosis recurrence after the first episode of stent

thrombosis is worrisome. Armstrong et al reported on a combined ret-

rospective and prospective observational California registry of angio-

graphic definite stent thrombosis at five academic hospitals from 2005

to 2013.

248

The entry criterion was the occurrence of a definite stent

thrombosis, which was observed in 221 patients overall out of an

unknown number of patients at risk. With the important caveat of not

knowing for each stent type the exact timing of the first stent thrombo-

sis event after the index procedure, 104 (47%) patients had received a

first generation DES, 51 (23%) a BMS, and 19 (9%) a second generation

DES. After a median follow-up of 3.3 years, 29 patients developed defi-

nite or probable recurrent stent thrombosis, while 19 presented angio-

graphic definite recurrent stent thrombosis. The cumulative hazard of

definite or probable recurrent stent thrombosis was 16% at 1 year and

24% at 5 years. The cumulative hazard of angiographic definite recurrent

stent thrombosis was 11% at 1 year and 20% at 5 years. Taken together,

these findings confirm the high risk of stent thrombosis recurrence after

the first stent thrombosis. An additional piece of information, which is

conveyed by this important analysis, is that the risk of recurrence is high-

est in the first few months after the first event and that it does not abate

entirely over time. Both prasugrel and ticagrelor have been shown to

be associated with a significant reduction of definite and definite or

probable stent thrombosis as compared to clopidogrel.

20,23

Moreover,

both studies indicated that the number of recurrent events is also signifi-

cantly decreased by treatment with ticagrelor or prasugrel as compared

to clopidogrel. Hence, the use of clopidogrel after stent thrombosis

cannot be regarded as an effective treatment option. Considering the

long-term risk of recurrence after first stent thrombosis, it may be rea-

sonable to make every effort to maintain DAPT for a very long-term

period in this highly selected high-risk patient population, if tolerated.

9.6 Patients who develop bleeding while

on treatment

Patients who develop bleeding complications while on DAPT repre-

sent a challenging patient population for whom no guidance from

RCTs is available.

The decision to withhold or continue DAPT in this setting largely

depends on ischaemic (e.g. indication for DAPT and time from last

stent insertion, if any, to bleeding) vs. recurrent/prolonged bleeding

risks. A practical flow chart in order to manage this challenging popu-

lation is provided in Figure 10 and additional information on practical

management can be found elsewhere.

249

As bleeding is an independ-

ent predictor of recurrent bleeding,

250

type, dose, and duration of

DAPT should be reassessed in this setting.

Gender considerations and special populations

Recommendations Class

Level

Similar type and duration of DAPT are rec-

ommended in male and female

patients.

26,240

I A

It is recommended to reassess the type,

dose, and duration of DAPT in patients with

actionable bleeding complications while on

treatment.

I C

Similar type and duration of DAPT should

be considered in patients with and without

diabetes mellitus.

145,242

IIa B

Prolonged (i.e. >12 months

) DAPT dura-

tion should be considered in patients with

prior stent thrombosis, especially in the

absence of correctable causes (e.g. lack of

adherence or correctable mechanical stent-

related issues).

IIa C

Prolonged (i.e. >12 months) DAPT duration

may be considered in CAD patients with

LEAD.

140,246

IIb B

Prolonged (i.e. >6 months) DAPT duration

may be considered in patients who under-

went complex PCI.

247

IIb B

CAD = coronary artery disease; DAPT = dual antiplatelet therapy; LEAD =

lower-extremities artery disease; PCI = percutaneous coronary intervention.

Class of recommendation.

Level of evidence.

Possibly for as long as can be tolerated.

Complex PCI deﬁned as the composite of at least three stents implanted, at

least three lesions treated, bifurcation with two stents implanted, total stent

length >60 mm, and chronic total occlusion as target lesion.

248 ESC Guidelines

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10. Key messages

(1) Benefits and risks of DAPT: DAPT reduces the risk of stent throm-

bosis across the entire spectrum of events, from acute to very late

occurrences. However, treatment with DAPT beyond 1 year after

MI, or after PCI, exerts the majority of its benefit by reducing the

rate of spontaneous MI. The risk of bleeding in patients on DAPT is

proportionally related to its duration both within and beyond

1 year of treatment duration. Since the benefits of prolonged

DAPT, especially for mortality endpoints, appear highly dependent

on prior cardiovascular history (such as prior ACS/MI vs. stable

CAD), and prediction models to estimate on-DAPT bleeding risk

have been developed, an individualized approach based on ischae-

mic vs. bleeding risk assessment is warranted.

(2)

Bleeding mitigation strategy: Every effort should be pursued to mit-

igate the risk of bleeding complications while the patient is on

DAPT, including access site selection, modulation of modifiable

risk factors for bleeding, low dose aspirin, low dose of P2Y12

inhibitor as appropriate, and routine use of PPI.

(3) P2Y

inhibitor selection: Clopidogrel is considered the default

P2Y

inhibitor in patients with stable CAD treated with PCI,

those with indication to concomitant oral anticoagulation, as well

as in ACS patients in whom ticagrelor or prasugrel are contraindi-

cated. Ticagrelor or prasugrel is recommended in ACS patients

unless drug-specific contraindications exist.

(4) Timing of P2Y

inhibitor initiation: The timing of initiation of a

P2Y

inhibitor is both drug- (i.e. ticagrelor or clopidogrel vs. pra-

sugrel) and disease-specific (i.e. SCAD vs. ACS and type thereof).

(5)

Stable CAD patients treated with PCI: Irrespective of the type of met-

allic stent implanted, the duration of DAPT is 1–6 month(s) depending

on the bleeding risk. For patients in whom the ischaemic risk prevails

over the risk of bleeding, a longer DAPT duration may be considered.

(6)

Metallic stent type and DAPT duration: The need for a short

DAPT regimen should no longer justify the use of BMS instead of

newer-generation DES. DAPT duration in each individual patient

should be guided by an individualized approach based on ischaemic

vs. bleeding risk assessment and not by the stent type.

(7) Stable CAD patients treated with CABG: There is insufficient data

to recommend DAPT in this patient population.

(8)

ACS patients: Irrespective of the final revascularization strategy

(e.g. medical therapy, PCI, or CABG), the default DAPT duration

in these patients is 12 months. Six-month therapy duration should

be considered in high bleeding risk patients, whereas >12-month

therapy may be considered in ACS patients who have tolerated

DAPT without a bleeding complication.

(9)

Patients with indication for oral anticoagulation: Compared with

OAC therapy alone, the addition of DAPT to OAC therapy results

in at least a two- to three-fold increase in bleeding complications.

Therefore, these patients should be considered at high risk of

bleeding and the indication for OAC should be reassessed and

treatment continued only if a compelling indication exists.

The duration of triple therapy should be limited up to a maximum

of6monthsoromittedafterhospitaldischarge,takingintoaccount

the ischaemic (e.g. complexity of treated CAD, amount of disease

left untreated, technical considerations regarding stent implantation

techniques, and results) as well as the bleeding risk. The use of tica-

grelor or prasugrel in this setting is not recommended.

(10)

Patients undergoing elective non-cardiac surgery after coronary stent

implantation: A multidisciplinary expert team should be considered

for pre-operative evaluation of patients with an indication for DAPT

before elective surgery. Scheduled surgery requiring discontinuation

of the P2Y

inhibitor should be considered after at least 1 month,

irrespective of the stent type, if aspirin can be maintained throughout

the perioperative period. If both oral antiplatelet agents have to be

discontinued perioperatively, a bridging strategy with cangrelor, tirofi-

ban, or eptifibatide may be considered, especially if surgery has to be

performed within 1 month after stent implantation.

(11)

Gender consideration and special populations: Similar type and dura-

tion of DAPT are recommended in male and female patients, as well

as in patients with and without diabetes mellitus. Patients with prior

stent thrombosis, especially in the absence of correctable causes,

should receive prolonged DAPT. A prolonged DAPT regimen may

also be considered in patients with LEAD or who have undergone

complex PCI. It is recommended to reassess the type, dose, and dura-

tion of DAPT in patients with actionable bleeding complications while

on treatment. In patients with active bleeding while on DAPT, the

decision to stop both antiplatelet agents, especially if shortly after PCI,

should be taken only if the bleeding is life-threatening and the source

has not been or cannot be treated. In such a rare case scenario, the

patient should be transferred to a primary PCI facility centre.

11. Evidenced-based ‘to do and

not to do’ messages

Recommendations that are class I or III with a level of evidence A or B

Recommendations on P2Y

inhibitor selection and timing Class

Level

In patients with ACS, ticagrelor (180 mg loading dose, 90 mg b.i.d.) on top of aspirin is recommended, regardless of initial

treatment strategy, including patients pre-treated with clopidogrel (which should be discontinued when ticagrelor is com-

menced) unless there are contraindications.

I B

In patients with ACS undergoing PCI, prasugrel (60 mg loading dose, 10 mg o.d.) on top of aspirin is recommended for P2Y

inhibi-

tor-naı¨ve patients with NSTE-ACS or initially conservatively managed STEMI if indication for PCI is established, or in STEMI patients

undergoing immediate coronary catheterization unless there is a high risk of life-threatening bleeding or other contraindications.

I B

Continued

ESC Guidelines 249

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Pre-treatment with a P2Y

inhibitor is generally recommended in patients in whom coronary anatomy is known and the

decision to proceed to PCI is made, as well as in patients with STEMI.

I A

Clopidogrel (600 mg loading dose, 75 mg o.d.) on top of aspirin is recommended in stable CAD patients undergoing

coronary stent implantation and in ACS patients who cannot receive ticagrelor or prasugrel, including those with prior

intracranial bleeding or indication for OAC.

I A

Clopidogrel (300 mg loading dose in patients aged <_75, 75 mg o.d.) is recommended on top of aspirin in STEMI patients

receiving thrombolysis.

I A

In NSTE-ACS patients in whom coronary anatomy is not known, it is not recommended to administer prasugrel.

III B

Measures to minimize bleeding while on dual antiplatelet therapy

Radial over femoral access is recommended for coronary angiography and PCI if performed by an expert radial operator.

I A

In patients treated with DAPT, a daily aspirin dose of 75 - 100 mg is recommended.

I A

A PPI in combination with DAPT is recommended.

I B

Routine platelet function testing to adjust antiplatelet therapy before or after elective stenting is not recommended.

III A

Switching between oral P2Y

inhibitors

In patients with ACS who were previously exposed to clopidogrel, switching from clopidogrel to ticagrelor is

recommended early after hospital admission at a loading dose of 180 mg irrespective of timing and loading dose of

clopidogrel, unless contraindications to ticagrelor exist.

I B

Dual antiplatelet therapy duration in patients with acute coronary syndrome treated with percutaneous coronary intervention

In patients with ACS treated with coronary stent implantation, DAPT with a P2Y

inhibitor on top of aspirin is

recommended for 12 months unless there are contraindications such as excessive risk of bleeding (e.g.

PRECISE-DAPT >_25).

I A

Dual antiplatelet therapy duration in patients with acute coronary syndrome undergoing medical therapy management

In patients with ACS who are managed with medical therapy alone and treated with DAPT, it is recommended to continue

P2Y

inhibitor therapy (either ticagrelor or clopidogrel) for 12 months.

I A

Ticagrelor is recommended over clopidogrel, unless the bleeding risk outweighs the potential ischaemic beneﬁt.

I B

Prasugrel is not recommended in medically managed ACS patients.

III B

Dual antiplatelet therapy in patients undergoing elective cardiac and non-cardiac surgery

It is recommended to continue aspirin perioperatively if the bleeding risk allows, and to resume the recommended

antiplatelet therapy as soon as possible post-operatively.

I B

It is not recommended to discontinue DAPT within the ﬁrst month of treatment in patients undergoing elective non-cardiac

surgery.

III B

Gender considerations

Similar type and duration of DAPT are recommended in male and female patients.

I A

ACS = acute coronary syndrome; CAD = coronary artery disease; DAPT = dual antiplatelet therapy; NSTE-ACS = non-ST elevation acute coronary syndrome; OAC = oral

anticoagulant; PCI = percutaneous coronary intervention; PPI = proton pump inhibitor; PRECISE-DAPT = PREdicting bleeding Complications In patients undergoing Stent

implantation and subsEquent Dual Anti Platelet Therapy; STEMI = ST-elevation myocardial infarction; TIA = transient ischaemic attack.

Class of recommendation.

Level of evidence.

Contraindications for ticagrelor: previous intracranial haemorrhage or ongoing bleeds. Contraindications for prasugrel: previous intracranial haemorrhage, previous ischaemic

stroke or TIA, or ongoing bleeds; prasugrel is not recommended for patients >_75 years of age or with a body weight <60 kg.

While the evidence that a PPI does not increase the risk of cardiovascular events was generated with omeprazole, based on drug–drug interaction studies, omeprazole and

esomeprazole would appear to have the highest propensity for clinically relevant interactions, while pantoprazole and rabeprazole have the lowest.

250 ESC Guidelines

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12. Web addenda and Clinical

Cases companion document

All Web figures, Web tables, and the Clinical Cases companion docu-

ment are available at the European Heart Journal online and also via

the ESC Web site at: www.escardio.org/guidelines

13. Appendix

ESC Committee for Practice Guidelines (CPG): Stephan

Windecker (Chairperson) (Switzerland), Victor Aboyans (France),

Stefan Agewall (Norway), Emanuele Barbato (Italy), He´ctor Bueno

(Spain), Antonio Coca (Spain), Jean-Philippe Collet (France), Ioan

Mircea Coman (Romania), Veronica Dean (France), Victoria Delgado

(The Netherlands), Donna Fitzsimons (UK), Oliver Gaemperli

(Switzerland), Gerhard Hindricks (Germany), Bernard Iung (France),

Peter Ju¨ni (Canada), Hugo A. Katus (Germany), Juhani Knuuti

(Finland), Patrizio Lancellotti (Belgium), Christophe Leclercq

(France), Theresa McDonagh (UK), Massimo Francesco Piepoli

(Italy), Piotr Ponikowski (Poland), Dimitrios J. Richter (Greece),

Marco Roffi (Switzerland), Evgeny Shlyakhto (Russia), Iain A. Simpson

(UK), and Jose Luis Zamorano (Spain)

ESC National Cardiac Societies actively involved in the

review process of the 2017 ESC focused update on dual

antiplatelet therapy in coronary artery disease in collabora-

tion with EACTS:

Austria: Austrian Society of Cardiology, Franz Xaver Roithinger;

Azerbaijan: Azerbaijan Society of Cardiology, Farid Aliyev;

Belarus: Belorussian Scientific Society of Cardiologists, Valeriy

Stelmashok; Belgium: Belgian Society of Cardiology, Walter

Desmet; Bulgaria: Bulgarian Society of Cardiology, Arman

Postadzhiyan; Cyprus: Cyprus Society of Cardiology, Georgios P.

Georghiou; Czech Republic: Czech Society of Cardiology, Zuzana

Motovska; Denmark: Danish Society of Cardiology, Erik Lerkevang

Grove; Estonia: Estonian Society of Cardiology, Toomas Marandi;

Finland: Finnish Cardiac Society, Tuomas Kiviniemi; The Former

Yugoslav Republic of Macedonia: Macedonian Society of

Cardiology, Sasko Kedev; France: French Society of Cardiology,

Martine Gilard; Germany: German Cardiac Society, Steffen

Massberg; Greece: Hellenic Society of Cardiology, Dimitrios

Alexopoulos; Hungary: Hungarian Society of Cardiology, Robert

Gabor Kiss; Iceland: Icelandic Society of Cardiology, Ingibjorg Jona

Gudmundsdottir; Ireland: Irish Cardiac Society, Euge`ne P.

McFadden; Israel: Israel Heart Society, Eli Lev; Italy: Italian

Federation of Cardiology, Leonardo De Luca; Kazakhstan:

Association of Cardiologists of Kazakhstan, Akhmetzhan Sugraliyev;

Kosovo: Kosovo Society of Cardiology, Edmond Haliti;

Kyrgyzstan: Kyrgyz Society of Cardiology, Erkin Mirrakhimov,

Latvia: Latvian Society of Cardiology, Gustavs Latkovskis;

Whatisnewinthe2017ESCfocussedupdateonDAPT?

New/revised concepts

Metallic stent and DAPT duraon

Switch between P2Y

inhibitors

Risk scores to guide DAPT duraon

− PRECISE DAPT score

−

DAPT score

Speciﬁc proﬁling

− Deﬁnion of complex PCI

−

Unfavourable proﬁle for OAC and APT

− Gender consideraons and

special populaons

DAPT duraon without stenng

− Medical management

− CABG or cardiac surgery

Ancoagulaon and DAPT

− Acute and chronic seng

− Dosing regimen

Pretreatment with P2Y

inhibitors

when PCI is planned

Liberal use of PPI to migate GI bleeding

risk

Ticagrelor interrupon of 3 days prior

elecve surgery

Roune platelet funcon tesng to adjust

therapy

Dual therapy as an alternave to triple

therapy when bleeding risk outweighs the

ischaemic risk

Change in recommendaons

Disconnuaon of P2Y

inhibitor therapy

aer 6 months when stenng ACS paents

with PRECISE-DAPT ≥ 25

New recommendaons 2017

7102erofeB

Disconnuaon of anplatelet treatment

in paents treated with OAC should be

considered at 12 months.

The occurrence of aconable bleeding while

on DAPT should prompt reconsideraon of

type and duraon of DAPT regimen.

The decision for DAPT duraon should be

dynamic and reassessed during the course

of the inially selected DAPT regimen.

IIB

6-month DAPT regimen In paents with

SCAD treated with drug-coated balloon

Ticagrelor 60 mg b.i.d preferred over other

oral P2Y

inhibitors for DAPT connuaon

>12 months in post-MI

III

IIA

Early administraon of cagrelor/ clopidogrel

in NSTE-ACS with invasive approach

Elecve surgery requiring disconnuaon

of the P2Y

inhibitor aer 1 month

ACS ¼ acute coronary syndrome; APT ¼ anti-platelet therapy; CABG ¼ coronary artery bypass graft; DAPT ¼ dual antipla-

telet therapy; MI ¼ myocardial infarction; NSTE¼ Non-st-segment elevation; OAC ¼ oral anti-coagulant;PCI ¼ percuatenous

coronary intervention; PRECISE-DAPT ¼ PREdicting bleeding Complications In patients undergoing Stent implantation and

subsEquent Dual Anti Platelet Therapy; Stable CAD ¼ stable coronary artery disease.

ESC Guidelines 251

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Lithuania: Lithuanian Society of Cardiology, Birute Petrauskiene;

Luxembourg: Luxembourg Society of Cardiology, Steve Huijnen;

Malta: Maltese Cardiac Society, Caroline Jane Magri; Morocco:

Moroccan Society of Cardiology, Rhizlan Cherradi; The

Netherlands: Netherlands Society of Cardiology, Jurrien M Ten

Berg; Norway: Norwegian Society of Cardiology, Jan Eritsland;

Poland: Polish Cardiac Society, Andrzej Budaj; Portugal:

Portuguese Society of Cardiology, Carlos Tavares Aguiar; Russian

Federation: Russian Society of Cardiology, Dmitry Duplyakov; San

Marino: San Marino Society of Cardiology, Marco Zavatta; Serbia:

Cardiology Society of Serbia, Nebojsa M. Antonijevic; Slovakia:

Slovak Society of Cardiology, Zuzana Motovska; Slovenia: Slovenian

Society of Cardiology, Zlatko Fras; Spain: Spanish Society of

Cardiology, Antonio Tello Montoliu; Sweden: Swedish Society

of Cardiology, Christoph Varenhorst; Switzerland: Swiss Society of

Cardiology, Dimitri Tsakiris; Tu n i s i a : Tunisian Society of Cardiology

and Cardio-Vascular Surgery, Faouzi Addad; Turkey: Turkish

Society of Cardiology, Sinan Aydogdu; Ukraine: Ukrainian

Association of Cardiology, Alexander Parkhomenko; United

Kingdom: British Cardiovascular Society, Tim Kinnaird.

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